Clandestine Manufacture of
Amphetamine from Benzaldehyde:
A n Investigative Analysis of its Synthesis
This thesis is presented to the Centre for Forensic Science of
The University of Western Australia as a part of the requirements for the degree of
Master of Forensic Science.
The work recorded in this thesis was carried out during 2000 to 2001 at the
Chemistry Centre of W A under the supervision of Dr D. Reynolds and at the University
of Western Australia under the supervision of Associate Professor E.L. Ghisalberti.
November 2001
Michael B. Tolmie
B.Sc. (Hons), Grad. Dip. Ed.
i
I dedicate this thesis to m y parents
whose love and belief in m y ability
has been steadfast.
11
Acknowledgments
I would like to thank Mr Colin Priddis for giving the opportunity to work within his
team and for all his help throughout the year.
I would like to express my appreciation to my supervisor Dr Dominic Reynolds for his
guidance, encouragement and sense of humour through the year.
I would like to thank Associate Professor Emilio Ghisalberti for his advice, patience
and support.
I would like to thank everybody in the Forensic Science Unit (WA) and the Chemistry
Centre ( W A ) for generously giving up their time to answer m y questions.
Finally, my sincerest gratitude to my family for their continued support throughout my
years of study.
m
Abstract
A number of chemicals from clandestine amphetamine laboratories were seized in
Perth, Western Australia. A common element to all of these laboratories was the
chemicals and 'homemade' equipment used. T w o of the chemicals recovered from the
laboratories, ammonium carbonate and zinc, are not normally associated with
amphetamine manufacture. Typed and hand written 'recipes' were also found at two of
the laboratories. The research described here is concerned with an investigation of the
possible synthetic routes employed in the manufacture of amphetamine. The variation
in yields with varying reaction conditions has also been examined. The likely role of
ammonium carbonate and zinc in the sequence is suggested and the use of alternative,
easily obtainable reagents in some reactions has been considered. This information can
be used to provide a more accurate estimation of the yield of this reaction for court
proceedings, and to determine past and future production, an aspect which is crucial in
the sentencing of manufacturers of illicit drugs.
IV
Abbreviations used in the text
ABCI
ACT
AFP
Adrenalin
Amphetamine
b.p.
CDL
Dopamine
Ephedrine
Eq
FT-IR
GC-MS
HPLC
Pseudoephedrine
MDA
MDMA
Methylamphetamine
mol
mmol
m.p.
Noradrenaline
P2P
PVC
TFA
Australian Bureau of Criminal Intelligence
Australian Capital Territory
Australian Federal Police
Epinephrine
2-Amino-l-phenylpropane
boiling point
Clandestine drug laboratory
4- (2 -Aminoethyl)-l,2 -benzenediol
1 -Phenyl-1 -hydroxy-2-(aminomethyl)propane
equivalents
Fourier Transform Infrared Spectroscopy
Gas Chromatography Mass Spectrometry
High Performance Liquid Chromatography
1 -Phenyl-1 -hydroxy-2-(aminomethyl)propane
3,4-Methylenedioxyamphetamine
3,4-Methylenedioxymethylamphetamine
1 -Phenyl-2 - (aminomethyl)propane
moles
milli moles
melting point
(R)-4-(2-amino-l -hydroxyethyl)-!, 2-Benzenediol
1 -Phenyl-2 -propanone
Polyvinylchloride
Trifluoroacetic acid
V
Contents
Page
Title i
Dedication ii
Acknowledgments iii
Abstract iv
Abbreviations used in the text v
Contents vi
Chapter One 1-8
1. Introduction 1
1.1. Effects of amphetamine use 2
1.2. Amphetamine seizures 2
1.3. Clandestine laboratories seizures 3
1.4. Health and Safety 4
1.5. Prosecution 4
1.6. Manufacturing methods 5
1.7. Case report 6
1.8. Research Objectives 6
1.9. References 8
Chapter Two 9-14
2. Syntheses of l-Phenyl-2-nitropropene 9
2.1. Western Australian method 10
2.2. Results and Discussion 11
2.3. Conclusion 13
2.4. References 14
vi
Chapter Three 15-31
3. Syntheses of l-Phenyl-2-propanone 15
3.1. Methods of manufacture 15
3.2. Western Australian method 20
3.3. Results and Discussion 21
3.3.1. Synthesis of l-Phenyl-2-propanone 21
3.3.2. Other metals 22
3.3.3. T w o phase solvent system 24
3.3.4. Reactivity of l-Phenyl-2-propanone 24
3.3.5. Varying the combination of reactants 24
3.3.6. Extraction with toluene 24
3.3.7. Synthesis of l-Phenyl-2-propanone and Purification 25
3.3.8. Clandestine method (experiment based on handwritten notes) 25
3.3.9. One pot conversion of benzaldehyde to l-phenyl-2-propanone 26
3.4. Determination of P2P in Clandestine reaction mixtures 27
3.5. Conclusion 28
3.6. References 30
Chapter Four 32-42
4. Syntheses of N-Formylamphetamine 32
4.1. Western Australian method 34
4.2. Results and Discussion 35
4.2.1. Commercial grade l-phenyl-2-propanone 35
4.2.2 Reaction with formamide 35
4.2.3. Reaction with formamide and formic acid 36
4.2.4. Reaction with ammonium formate 37
4.2.5. Reduction with ammonium formate in excess formic acid 37
4.2.6. Procedure used in clandestine laboratory 37
Vll
4.2.7. Impure l-phenyl-2-propanone 38
4.2.8. Reaction with formamide 38
4.2.9. Reaction with formamide and formic acid 38
4.2.10. Reaction with ammonium formate 39
4.2.11. Reaction with ammonium formate/excess formic acid 39
4.3. Conclusion 40
4.4. References 41
Chapter Five 43-47
5. Syntheses of Amphetamine 43
5.1. Results and Discussion 46
5.2. Conclusion 46
5.3. References 46
Chapter Six 48-50
6. Summary: Synthesis of amphetamine from benzaldehyde 48
Chapter Seven 51-63
Experimental
7. General 51
7.1. Materials 53
7.2. Preparation of Compounds 53
7.2.1. Syntheses of l-Phenyl-2-nitropropene 53
7.2.2. Syntheses of l-Phenyl-2-propanone 55
7.2.3. Syntheses of N-Formylamphetamine 59
7.2.3.1. Leuckart reactions using commercial l-phenyl-2-propanone 59
7.2.3.2. Leuckart reactions using impure l-phenyl-2-propanone 61
7.2.4. Synthesis of Amphetamine 62
7.3. References 63
Appendix
Vlll
64
Chapter One
1. Introduction
Amphetamines are potent psychomotor stimulants that directly affect the central
nervous system (CNS). Their use causes a release of excitatory neurotransmitters
dopamine and noradrenaline from storage vesicles in the C N S . The generic term
"amphetamines" is used to describe compounds that incorporate the phenylethylamine
pharmacophore, and includes drugs such as pseudoephedrine, phentermine,
dextroamphetamine, methylamphetamine, methylenedioxyamphetamine ( M D A ) and
ecstasy ( M D M A ) . Some of these have become popular drugs of abuse and thus, targets
for clandestine laboratories for over 50 years.1 Particular amphetamines can be
acquired legally by prescription, however their medical uses are limited and include the
treatment of respiratory congestion, childhood hyperactivity, obesity and narcolepsy, a
rare disorder in which persons often lapse into deep sleep.
HO,
HO'
Dopamine
NHR
R= H, Noradrenaline
R=CH3, Adrenaline
^nf
Pseudoephedrine
^ = -
Phentermine
^ ^ NHR
R=H, Amphetamine
R=CH3, Methylamphetamine
NHR
\-6 R=H, MDA
R=CH3, MDMA
1
1.1. Effects of amphetamine use
Since the mid-1980s, illicit use of amphetamines has remained a significant problem in
Australia. Amphetamines are the most commonly used illicit drugs after cannabis,
with approximately 9 % of the population having used them. They are particularly
common among younger groups, as many as 2 1 % of 20 to 29 year olds have become
long term users.2
Amphetamines can be administered orally, by inhalation or intravenous injection. High
doses of amphetamines, especially by injection, can result in a form of schizophrenic
paranoid psychosis, delusions and hallucinations.
However psychosis is not the only psychological outcome associated with regular
amphetamine use. High proportions of users demonstrate symptoms such as anxiety,
panic attacks, paranoia and depression. The emergence of such symptoms is associated
with injection of the drugs, greater frequency of use and dependence upon
amphetamines.1 The estimated direct health care cost of drug dependence and harmful
use of drugs in Australia in 1992 was $1.0 billion, of which $43 million is the cost
arising from the use of illicit drugs.3
1.2. Amphetamine seizures
During 1999-2000, Australian Customs seized 21.5 kilograms of amphetamines
destined for the Australian market. Although the number of seizures (60) were nine
less than those recorded for the previous year4, the average weight of amphetamine per
seizure increased from 145 grams to 358 grams.
Despite further seizures in 2000/01 by the Australian Federal Police (AFP) of
amphetamine-type substances totalling 412 kg, of which 152 kg was
methylamphetamine (Ice)5, large quantities of amphetamines continues to be produced
domestically. Domestic seizures of amphetamines during 1999-2000 totalled 4861
(where the drug weight was recorded), in which 381.3 kg were recovered, an increase
of 124.4 kg on the previous year (1998-1999).4
2
The samples of amphetamine seized in Australia is generally of low quality. Forensic
analysis of samples seized in 1999-2000 revealed that the amount of amphetamine
varied between 1 to 65 %.4 These results relate to unrepresentative sample, since
samples of drugs seized are analysed for forensic purposes only in contested court
cases.
1.3. Clandestine laboratories seizures
A Clandestine Drug Laboratory (CDL), by definition, is an illicit operation consisting
of sufficient combination of apparatus and chemicals that either have been or could be
used in the manufacture or synthesis of prohibited drugs.6 Such operations are
potentiality hazardous to the operator, neighbours, investigators and to the
environment. Police intelligence continues to link organised crime groups - among
them outlaw motorcycle gangs ( O M C G ) - to the manufacture and distribution of
amphetamine-type substances.
The Australian Bureau of Criminal Intelligence (ABCI) has reported that the number of
importations of amphetamines to Australia has decreased in recent years. This could
indicate that domestic production has increased, lessening the demand for costly and
high-risk imported substances. Statistics from Australian law enforcement agencies,
for the period 1997-2000, show that the number of seizures of clandestine laboratories
increased from 95 in 1997-1998 to 150 in 1999-2000. The greatest number of
clandestine laboratories were found in Queensland (Table l).4 The popularity of these
laboratories is due, in part, to the fact that amphetamine is easy to manufacture and the
starting materials are relatively inexpensive.
Table 1: Clandestine laboratory seizures, by State and Territory (1999-2000)
State/Territory*
N e w South
Wales
20
Victoria
18
Queensland
79
South Aust
14
Western
Aust
17
Northern
Territory
1
ACT
1
Total
150
*Note: N o clandestine laboratories were found in Tasmania (Source: ABCI).
3
1.4. Health and Safety
Frequently, it is found that operators in clandestine laboratories have little knowledge
or experience in chemistry. Thus, they face risks from corrosive chemicals, toxic
chemicals, fires and explosions. However, due in part to this inexperience, the illicit
manufacture of amphetamine also poses a risk to the end users, because the final
product is often contaminated with starting materials, by-products, and cutting agents
or diluents.
There are many controlled drugs that can be synthesised in clandestine laboratories and
a multitude of different methods of synthesis. A n aim of the present work was to
investigate methods, assumed or found to have been used recently at a number of
clandestine laboratories. Such information is of forensic importance. Each clandestine
laboratory is unique and presents different types of hazards. If the type of chemical
reaction used is known, it may be possible to avoid or reduce the risk of exposure to
both chemical and physical hazards that may be encountered by investigators. The
forensic chemist must be able to recognise reactions in progress and h o w to safely
handle them. A hazardous situation must be dealt with immediately and safely.
1.5. Prosecution
The offence of manufacturing or preparing a prohibited drug is covered in the Misuse
of Drugs Act, section 6(l)(b), in Western Australia. If the product seized already exists
within the original substance (eg ephedrine/pseudoephedrine is extracted from Sudafed
with methylated spirits), then the offence is classed as a step taken in the preparation.
If a chemical process is used to convert a particular chemical to another substance
(eg l-phenyl-2-propanone to amphetamine), then this is classed as a step in the
manufacture of a prohibited drug.6 Forensic chemists have a role in identifying
reagents and precursors found in clandestine laboratories. They must be able to
demonstrate that a particular drug was being synthesised, to explain fully in court all
steps in the synthesis and to disregard items of little or no evidentiary value.
4
The successful prosecution of clandestine laboratory operators depends on the forensic
chemist's thorough knowledge of the manufacturing procedure. Frequently, the
synthetic route used can be inferred from evidence of purchase of the chemical
precursors. Establishing the link between the purchase of these chemicals and those
found on the laboratory premises can be important to the prosecution.
The identification of by-products present in a sample of an illicit drug can be extremely
useful in establishing the method of synthesis used. If no finished product is available,
then analysing the seized unwashed laboratory equipment, residues and liquids can
provide the characteristics of the precursors used, by-products formed and indicate
traces of final product. This information often allows verification that a controlled
substance was being manufactured, or that an attempt was made for its production.
This "chemical fingerprinting" yields valuable information on the reaction sequence
used and on the expertise of the operator.
1.6. Manufacturing methods
A variety of synthetic methods for the production of amphetamine-type compounds are
available. One of the most common methods employed by clandestine laboratory
operators in Western Australia for the manufacture of amphetamine, has been the
reductive amination of l-phenyl-2-propanone (P2P) via the Leuckart reaction.
Scheme 1
^ 1 -Phenyl-2-nitropropene
Reduction
Hydrolysis
Reduction
^ ^
^ ^ N H 2
Amphetamine
Amination
1 -Phenyl-2-propanone
This approach involves the use of the precursor l-phenyl-2-nitropropene ((3-methyl-p-
nitrostyrene). This precursor may be synthesised from benzaldehyde and nitroethane
and converted directly to amphetamine under reducing conditions, or used to synthesise
P2P (Scheme 1).
5
1.7. Case Report
Clandestine Drug Laboratory Specialists assisted the Western Australian Police Service
in the seizure of a suspected amphetamine laboratory located in Perth. During an
examination of documents located at a number of premises, handwritten and typed
'recipes' for the manufacture of amphetamine were found. In conjunction with the
precursors and chemicals discovered on the site, and intermediates detected upon
analysis, it was possible to determine that a novel method was being used to
manufacture amphetamine.
The items seized from one crime scene included round bottom flasks, 20 L stainless
steel reaction vessels and homemade condensers (PVC tubing with glass or copper used
for internal liner and c o m m o n garden hose fittings for plumbing). Reagents and
solvents included 20 L drums of glacial acetic acid, toluene and formic acid,
ammonium carbonate (10 kg) and zinc powder (500 g). Precursors and intermediates
consisted of benzaldehyde (16 L), nitroethane (2.5 L), l-phenyl-2-nitropropene (1.4 kg)
and 1.0 L of liquid identified as l-phenyl-2-propanone. N-formylamphetamine and
amphetamine were present in a separatory funnel.
Based on the items seized and 'recipes' for the process, it was calculated that 1.4 kg of
l-phenyl-2-nitropropene would yield 500 g of amphetamine hydrochloride. In
addition, 16 g of amphetamine was identified in the separatory funnel and could be
recovered by separation and crystallisation as the hydrochloride salt. It was estimated
that approximately 6 kg of amphetamine hydrochloride could be produced from 16 L of
benzaldehyde available.
1.8. Research Objectives
The research presented in this thesis was undertaken for the purposes of establishing
the synthetic processes employed in a number of clandestine laboratories. This
information is useful in linking an illicit laboratory to seized material and also in
providing information on precursors and expertise involved in the production. It can
also allow the overall yield of the process to be estimated. This is important in
determining past and future production, an aspect which is crucial for court proceedings
and for sentencing purposes.
6
At a number of clandestine laboratories, some of the chemicals seized were not
normally associated with the manufacture of amphetamine. The likely use of these
chemicals needed to be established. The manufacturing process selected may reflect
the operator's desire to avoid chemicals that are likely to be monitored at chemical
supply companies by law enforcement agencies, and to substitute these chemicals with
those which attract less attention. The possibility that other reagents could be used in
some of these reactions was examined.
Scheme 2
O
H + CHoCH2NO
Benzaldehyde
3wi I 2 I N W 2
Nitroethane
^ ^
(1)
^ ^ CH3
1 -Phenyl-2-nitropropene
(2)
Amphetamine
^^^ H N ^ O
N-formylamphetamine H
^ ^
1 -Phenyl-2-propanone
In this thesis, the manufacturing process shown in Scheme 2 is considered in some
detail. Each step is considered in individual chapters and the more significant findings
are summarised in a separate chapter.
7
1.9. References
1. French, L.G., "The Sassafras Tree and Designer Drugs", Journal of Chemical
Education, 1995, 72 (6), 484 491.
2. Darke, S, Ross, J, Hando, J, Hall, W and Degenhardt, L., "Illicit Drug Use in
Australia Epidemiology, Use Patterns and Associated Harm", National Drug and
Alcohol Research Centre University of N e w South Wales Australia, 2000.
3. Australian Institute of Health and Welfare 1999. 1998 National Drug Strategy
Household Survey: First results. A I H W cat. No. P H E 15. Canberra: A I H W (Drug
Statistics Series).
4. Australian Bureau of Criminal Intelligence (ABCI) Australian Illicit Drug Report
1999-2000, March 2001.
5. Media Release. AFP confirm weight of amphetamines seized on southern
Queensland coasts. [Homepage of AFP], [Online]. Available
http://www.afp.gov.au [2001, 31 July].
6. Western Australian Police Service. Clandestine Laboratory Safety and
Investigation Course Manual, 2001.
8
Chapter Two
2. Syntheses of l-Phenyl-2-nitropropene
Nitroalkenes are readily synthesised in good yields.1 Using aromatic aldehydes,
nitroalkenes can be prepared in a single step as shown in Scheme 1. These nitroalkenes
have proven to be useful for the facile production of the homologous ketones.
Scheme 1
Primary
A r C H O + R C H 2 N 0 2 — — - — - ArCH=C(N0 2 ) R
Although this reaction was first carried out using zinc chloride as an acid catalyst, bases
such as alcoholic potassium hydroxide or alcoholic methylamine have normally been
used.2 Condensation of benzaldehyde with nitroethane using zinc chloride as a catalyst
afforded 1-phenyl-2-nitropropene in 5 6 % yield. A similar yield (52%) was obtained
when benzaldehyde and nitroethane, in 1:1.5 molar ratio, were allowed to react in the
presence of 5 % methanolic methylamine at room temperature for 3-7 days. Heating the
solution produced amounts of high melting polymers and reduced the yield. A slightly
higher yield (64%) was obtained by heating an ethanolic solution of equimolar amounts
of benzaldehyde and nitroethane in the presence of 0.05 mol eq. of butylamine for 8 hr.1
Ammonium acetate in acetic acid has also been used to achieve this reaction. Refluxing
an acetic acid solution of the reactants and ammonium acetate (0.5 mol eq.) for 2 hr
afforded the product in 5 5 % yield. The relatively high solubility of the product in acetic
acid might explain the lower yield. The use of butylamine3 or amylamine4 as catalysts
has been reported (Scheme 2). With 0.1 mol eq. of amylamine, a mixture of
benzaldehyde and nitroethane allowed to stand in the dark for 14 days afforded 1-phenyl-
2-nitropropene in 7 5 % yield.4
9
A two step approach to the synthesis of the nitroalkene did not improve the yield. In this
reaction, the imine was first prepared by heating benzaldehyde with butylamine in
benzene. Acetic acid and one equivalent of nitroethane were added to the imine and the
mixture was heated under reflux for 1 hr to give the nitroalkene in 6 1 % yield.5
Scheme 2
O
H + CH3CH2NO
^ y ^
Benzaldehyde Nitroethane
Butylamine
2 reflux 3-4 hrs, or let stand in dark several days V ^
1 -Phenyl-2-nitropropene
2.1. Western Australian method
Over the past three years in Western Australia (WA), four clandestine laboratories
where amphetamine was being produced were uncovered. Similar chemicals were
seized from each of these laboratories: benzaldehyde, nitroethane, ammonium
carbonate, formic acid, acetic acid and zinc powder. A minimum amount of glassware
was found and the equipment used was often homemade.
The aim of the work described in this section was to establish the method(s) used for
the first step in the preparation of amphetamine, to determine the possible yield and
plausible variations. It was assumed that benzaldehyde and nitroethane were
condensed using ammonium carbonate in acetic acid as the catalyst. Large quantities
of ammonium carbonate (10 kg) and acetic acid (20 L) were found at a number of sites.
Scheme 3
H
O (NH4)2C03
Benzaldehyde
+ C H 3 C H 2 N 0 2 Acetic acid ^ ^ ^
Nitroethane 1 -Phenyl-2-nitropropene
10
2.2. Results and Discussion
The yields of l-phenyl-2-nitropropene obtained from the reaction of benzaldehyde and
nitroethane with ammonium carbonate as the catalyst were determined for various
concentrations of the three components (Table 1). For comparison, the effect of using
butylamine as the catalyst was also investigated. A method described in a 'recipe'
seized at a clandestine site, but obtained after most of the work described here was
completed, was also repeated. In each case, the progress of the reactions was
monitored by G C - M S analysis.
Table: l-Phenyl-2-nitropropene
Benzaldehyde
0.1 mol
0.92 mol
75 mmol
0.15 mol
0.03 mol
97 mmol
Nitroethane
0.1 mol
0.92 mol
50 mmol
0.1 mol
0.02 mol
98 mmol
Catalyst
0.01 mol eq.(NH4)2C03
0.01 mol eq. (NH4)2C03
0.25 mol eq. (NH4)2C03
0.25 mol eq. Butylamine
0.1 mol eq. Butylamine
0.25 mol eq. (NH4)2C03
Reaction
Time (Hours)
2
2
6
3
4
1
Yield (%)
22.5
47
54
53
62
39*
* Method followed from an actual recipe seized at a clandestine laboratory site.
In the first reaction, 0.01 mol eq. of ammonium carbonate was added to equimolar
(0.1 mol) amounts of benzaldehyde and nitroethane in acetic acid. The mixture was
heated under reflux for 2 hr, although G C - M S analysis indicated that the reaction was
essentially complete after 1 hr. Recovery of the product afforded l-phenyl-2-
nitropropene in 22.5% yield. The product was characterised by J H - N M R and FT-IR
spectroscopy (Fig. 1 and 5, appendix), and from the melting point. As expected, the
double bond has the .E-configuration. This is deduced from the chemical shift of the
vinylic proton at 5 8.1, in agreement with that observed for the .E-isomer and not for
that observed (8 6.3) for the Z-isomer.6
11
This reaction was repeated on a ten-fold scale and the yield of the product recovered
increased to 4 7 % . The increase in yield probably reflects the relatively smaller loss of
material in a large scale reaction.
A third experiment was carried out using benzaldehyde and nitroethane in a 1.5:1 ratio.
The amount of catalyst was increased to 2 5 % and the reaction was allowed to proceed
for 6 hours. This afforded l-phebnyl-2-nitropropene in 5 4 % yield
Reactions using the same ratio of reactants and 0.25 mol eq. and 0.1 mol eq. of
butylamine afforded the product in 5 3 % and 6 2 % yields, respectively. The yield in the
second of these experiments is in good agreement to that (64%) obtained by Hass et al}
using 5 % butylamine as catalyst.
The final experiment was based on a method described in a 'recipe' seized at a
clandestine laboratory site. Benzaldehyde, nitroethane and ammonium carbonate were
combined in a molar ratio of 1:1:0.25 in excess acetic acid. The mixture was heated
under reflux for 1 hr. Work-up gave the nitroalkene in 3 9 % yield.
There were a number of differences in the clandestine synthesis compared to the
laboratory synthesis. In the clandestine synthesis, ammonium carbonate was first
added to acetic acid, followed by nitroethane. It was emphasised that benzaldehyde be
added last. After heating for 1 hr, the mixture was poured into a bucket containing
crushed ice. Once the ice had melted, the water was decanted. The thick yellow oil
remaining at the bottom of the bucket was poured into a Buchner funnel where it
crystallised on attempted filtration. In the large-scale laboratory synthesis, comparable
amounts of nitroalkene (42%) could be recovered from the first crop of crystals. A n
additional 1 2 % could be obtained by extraction of the mother liquor by extraction with
toluene. For clandestine purposes, recovery of this extra material is not worth the extra
level of sophistication needed. Thus, an extraction solvent such as toluene, separatory
funnels (expensive and cumbersome to use for large-scale preparations), drying agents
and methods for removal of the solvent, are not required.
12
2.3. Conclusion
Benzaldehyde, nitroethane and ammonium carbonate in acetic acid heated under reflux
was found to produce l-phenyl-2-nitropropene in a yield comparable to that obtained
using catalysts such as butylamine. Presumably, the catalyst involved is ammonium
acetate. The best yield for this reaction was achieved using the three compounds in a
1.5:1.0:0.25 ratio and heating under reflux for 6 hr. The nitroalkene was obtained in
5 4 % yield with respect to nitroethane. G C - M S analysis showed that the m a x i m u m
yield was achieved after 1 hr.
The clandestine method required benzaldehyde, nitroethane and ammonium carbonate
in a molar ratio 1:1:0.25 and heating under reflux for 1 hr. The product, obtained in
3 9 % yield, is relatively pure and can be used in the next step without the need for
purification. Higher recovery of the product is sacrificed in order to simplify the
procedure. The simple nature of this reaction means that unskilled operators can
successfully produce this intermediate for the production of amphetamine. A m m o n i u m
carbonate, which is not a chemical closely monitored by law enforcement agencies, and
acetic acid offers a suitable and inexpensive substitute for butylamine as a catalyst in
the production of l-phenyl-2-nitropropene.
•J OQ
Initially it was planned to apply some form of simplex optimisation ' ' to the
experiments in order to achieve the optimal yield. The object of the experiment is to
optimise the relative yield of l-phenyl-2-nitropropene by simultaneously varying the
molar ratio of reactants and the relative reaction time applying statistical analysis to
the results.
Unfortunately this rationale could not be explored and a more conventional approach to
optimisation, by varying one factor at a time, may have been more appropriate in the
course of these experiments. Nonetheless reasonable estimates for the optimum
conditions have been established through the experiments described in this thesis.
13
2.4. References
1. Hass, H.B., Susie, A.G., and Heider, R.L., "Nitro Alkene Derivatives", Journal
of Organic Chemistry, 1950, 15, 8-14.
2. Gairaud, C.B. and Lappin, G.R., "The Synthesis of co-Nitrostyrenes", Journal of
Organic Chemistry, 1953,18, 1-3.
3. Barbato, J.J., "Identification of l-Phenyl-2-Nitropropene", Microgram, 1990,
23, 35-36.
4. Alles, G.A., "d,/-5eta-Phenylisopropylarnines", Journal of the American
Chemical Society, 1932, 54, 271-274.
5. DeRuiter, J., Clark, C.R. and Noggle, F.T., "Gas Chromatographic and Mass
Spectral Analysis of Amphetamine Products Synthesised from l-Phenyl-2-
Nitropropene", Journal of Chromatographic Science, 1994, 32, 511-519.
6. Leseticky, L., Flieger, M., Drahoradova, E., "Thermodynamics of E-Z-
Isomeration of P-Alkyl-(3-Nitrostyrenes", Collection of Czechoslovakian
Chemical Communications, 1976, 41, 2744-.
7. Chubb, L., Edward, J.T. and Wong, S.C., "Simplex optimisation of yields in the
Bucherer-Bergs reaction, " /. Org. Chem., 1980,45, 2315-2320.
8. Amenta, D.S., Lamb, C.E. and Leary, J.J., "Simplex optimisation of yield of
sec-butylbenzene in a Friedel-Crafts alkylation. A special undergraduate project
in analytical chemistry," /. Chem. Educ.,1919, 56, 557-558.
9. Dean, W.K., Heald, K.J. and Deming, S.N., "Simplex optimisation of reaction
yields," Science,l915, 189, 805-806.
14
Chapter Three
3. Syntheses of l-Phenyl-2-propanone
The sale and supply of chemicals known to be used in the illicit manufacture of drugs is
restricted. l-Phenyl-2-propanone (P2P) was included in the Seventh Schedule
controlled substance Poisons Act of Western Australia in August 1992. As a result of
agreements with the chemical supply industry all persons wanting to purchase
chemicals that can be used in the synthesis of illicit drugs are required to fill in an End
User Declaration ( E U D ) and must provide proper identification showing current
residency, as well as a full explanation for the request. All transactions involving the
sale or transfer of these chemicals may be reported to law enforcement agencies.
As a result of these tighter controls placed on l-phenyl-2-propanone, illicit drug
chemists are denied ready access to this starting material. It is therefore likely that
most clandestine laboratories engaged in reductive amination reactions in Australia
now use homemade l-phenyl-2-propanone.1
3.1. Methods of manufacture
Various methods for the synthesis of l-phenyl-2-propanone have been reported in the
literature. The most c o m m o n of these used in clandestine laboratories are listed below:
• Distillation of a mixture of lead salts of phenylacetic and acetic acids.
•">
• Pyrolysis of phenylacetic acid and acetic acid over thorium oxide.
• Treatment of phenylacetic acid with acetic anhydride, and sodium acetate or
pyridine.4
• Hydrolysis of a-phenylacetoacetonitrile with sulfuric acid.
• Friedel-Crafts alkylation of benzene with chloroacetone.
• Reduction of l-phenyl-2-nitropropene in the presence of iron, ferric chloride and
o
hydrochloric acid.
15
Scheme 1
Phenylacetic acid Lead (II) Acetate
dry distillation
^ ^ ^
1 -Phenyl-2-propanone
The dry distillation of equimolar amounts of phenylacetic acid and lead acetate over a
direct flame, followed by distillation of the product, provides 1 -phenyl-2-propanone in
3 6 % yield (Scheme 1). 2
Scheme 2
^ ^
Phenylacetic acid
H3CK o Thorium oxide catalyst
Tube furnace, 430-450°C
OH ^ ^
Acetic acid 1 -Phenyl-2-propanone
l-Phenyl-2-propanone can also be produced by reacting phenylacetic acid and acetic
acid (1:2 molar ratio) in a combustion tube containing a thorium oxide catalyst
(Scheme 2). After fractional distillation of the product, a yield of between 55 and 6 5 %
can be obtained.
^ t ^
Phenylacetic acid
Scheme 3
O
O H3CK
C H3C^(
O Acetic Anhydride
Pyridine
reflux 6hrs l ^ > ^
1 -Phenyl-2-propanone
Reaction of phenylacetic acid with excess acetic anhydride and pyridine under reflux
for six hours gave, after fractional distillation, l-phenyl-2-propanone in 5 6 % yield
(Scheme 3).4
16
Scheme 4
Sulfuric acid
" ^ C H 3
alpha-Phenylacetoacetonitrile
^ ^ ^
1 -Phenyl-2-propanone
Hydrolysis of oc-phenylacetoacetonitrile with aqueous sulfuric acid gave l-phenyl-2-
propanone in 77-86% yield (Scheme 4).5
Scheme 5
r^N CIH2C
^ ^ ^
Benzene
H> AICI,
H 3 C
Chloroacetone
^V^
1 -Phenyl-2-propanone
Friedel-Craft alkylation of benzene with chloroacetone also yields l-phenyl-2-
propanone. Chloroacetone in benzene is treated with 2 molar equivalents of
aluminium chloride under reflux for five hours. The mixture is extracted with benzene
and then distilled. l-Phenyl-2-propanone is recovered from the distillate via the
sodium bisulphite addition product, followed by steam distillation. The distillate is
extracted with ether, the ether evaporated and vacuum distilled to give a 3 2 % yield of
l-phenyl-2-propanone (Scheme 5).6
R ^ N ° 2
Nitroole -fin
Scheme 6
Raney Ni
H2Na02P R ^ 11
0 Ketone
The reduction of nitroolefins with metals, followed by hydrolysis, provides ketones in n t
excellent yield. A general procedure has been described by Monti et al. A suspension
of Raney nickel and an aqueous solution of sodium hypophosphite is added
17
(in several portions under stirring) to a solution of the nitroolefin in ethanol-aqueous
acetate buffer. After 2 hours at 40-60° C the catalyst was filtered off, water added and
the solution extracted with ether. Evaporation of the solvent yields the carbonyl
compound, which is purified by distillation. The reduction of l-phenyl-2-nitropropene
gives the ketone in 8 8 % yield (Scheme 6).
Scheme 7
^ x ^
1 -Phenyl-2-nitropropene
Fe, Ferric chloride HCI
» reflux ^ ^
1 -Phenyl-2-propanone
Hass et al. reported that when l-phenyl-2-nitropropene, 40 mesh cast iron turnings,
distilled water, ferric chloride and concentrated HCI were heated (85-95° C) for 5 to 6
hours, followed by distillation, gave l-phenyl-2-propanone in 7 5 % yield (Scheme 7).
Scheme 8
N 0 2 Zinc
25 % Acetic acid Ketoxime
H
R
2 M Sulfuric acid 4 0 % Formaldehyde
R'
O Ketone
The reduction of nitroolefins to the ketoxime intermediate using zinc powder and acetic
acid proceeds smoothly in 50-60% yield.9 The ketoximes can be hydrolysed to ketones
by refluxing with 2 molar sulfuric acid and a hydroxylamine acceptor (40%
formaldehyde). Yields of the ketone were reported to be around 8 0 % , with an over-all
yield from the nitroolefin of 40-48% (Scheme 8).
18
Scheme 9
H
Zn-TFA /k R̂'
o Ketone
The direct conversion of nitroolefins to the corresponding ketones with zinc/acetic acid
has been known for a long time.10 This reaction requires forcing conditions and long
reaction times and its application is limited to compounds that do not contain other
labile functional groups. However, this is not a problem for the preparation of
l-phenyl-2-propanone and other simple aryl ketones. It is worthwhile noting a recent
modification of this method.10 The use of stoichiometric amounts of
zinc/trifluoroacetic acid (TFA) in organic solvents such as dimethylformamide or
methanol greatly reduces the reaction time (from 3-6 hr to 15 min) and the temperature
required (ambient temperature) with a modest increase in yield (Scheme 9).
Scheme 10
NaBI-U/HA
R n4/n2w2 •'
K 2C0 3 ^ -
MeOH, 20h,r.t. o
A new practical procedure for the conversion of nitroalkenes into ketones uses
NaBH4/H 2 0 2 to give good yields (48-80%) of the ketone (Scheme 10).n
The methods illustrated above for the manufacture of l-phenyl-2-propanone are those
in which the chemical operations are not complicated. Many other synthetic routes for
l-phenyl-2-propanone, are known12, but are not important in the present context. The
most common synthesis for l-phenyl-2-propanone in Australia and in the western and
northwestern parts of the United States12 appears to be the reaction of phenylacetic acid
and acetic anhydride (Scheme 3).
19
3.2. Western Australian method
In Western Australia ( W A ) , the method using phenylacetic acid and acetic acid in a
tube furnace has been found only once in the past 7 years (Scheme 2). The most
frequently encountered method for the synthesis of l-phenyl-2-propanone in W A is the
reduction of l-phenyl-2-nitropropene with zinc in acetic acid (Scheme 11).
Scheme 11
1 -Phenyl-2-nitropropene Zinc metal 1 -Phenyl-2-propanone
The chemicals and equipment found at four separate clandestine laboratories were all
very similar. The precursor chemicals seized included large amounts of benzaldehyde,
nitroethane, ammonium carbonate, zinc powder, acetic acid and formic acid. From the
size of reaction vessels and quantities of materials seized, the illicit process was
probably being carried out in up to kilogram batches. It was postulated that ammonium
carbonate was being used as a base in the condensation reaction of benzaldehyde and
nitroethane to produce l-phenyl-2-nitropropene. Formic acid and ammonium carbonate
react to form ammonium formate, a reducing agent associated with the Leuckart
reaction. This suggested that reductive amination of l-phenyl-2-propanone was
involved. The presence of zinc powder, seized in 500g quantities, and acetic acid
indicated that these were used for the conversion of l-phenyl-2-nitropropene to
l-phenyl-2-propanone. Typed and hand written recipes found at the scene were not
received until the end of the present project. The aim of the following study was to
determine the yields under different reaction conditions for this reaction, to determine if
other metals could be substituted for zinc and if zinc could be used to replace other
metals in similar reactions.
20
3.3. Results and Discussion
The conversion of l-phenyl-2-nitropropene to the key amphetamine precursor
l-phenyl-2-propanone was investigated. Yields of l-phenyl-2-propanone by the
variation of concentration of reactants, temperature, time and solvent composition have
been determined. The l-phenyl-2-propanone used in these studies was synthesised
from l-phenyl-2-nitropropene in a one step process (scheme 11) and either isolated as
the crude reaction product or purified by vacuum distillation, silica gel chromatography
or steam distillation (Table 1).
Table 1: Conversion of l-phenyl-2-nitropropene to 1 -phenyl-2-propanone
Molar ratio of
nitrostyrene:zinc
1:5
1:5
1:5
1:5*
1:5*
1:5
1:2.5**
Reaction
Time
(Hours)
1.5
2
1.5
5
3
2
1
Solvent used in
extraction
Dichloromethane
Toluene
Toluene
Toluene
Toluene
None
None
Yield
(%)
19
27
32
43
26
53
39
Purification
method
N.A
N.A
N.A.
Vacuum distilled
Silica filtration
Steam distilled
Steam distilled
*An extra equivalent of zinc was added in some reactions as, when monitored by GC-MS,
starting material remained.
**Method followed from an actual recipe seized at a clandestine site.
N.A. - Not applicable.
3.3.1. Synthesis of l-phenvl-2-propanone
To l-phenyl-2-nitropropene in acetic acid, five equivalents of zinc were cautiously
added portionwise and the mixture was refluxed for 1.5 hr. Recovery of the product
by extraction with dichloromethane was 9 3 % , the yield of P2P from this reaction
(determined by GC-FID) was 19%. Increasing the reaction time to 2 and 4 hr. afforded
a yield of 8 % and 6.5 % respectively (determined by GC-FID). Each reaction was
monitored by G C - M S and was essentially complete in thirty minutes. The reduced
yields of the ketones is probably due more to the extraction technique, which was
21
hindered by the formation of emulsions, than to the reaction time. The spectral data,
G C - M S and FT-IR (Fig. 6, appendix), were consistent with those of l-phenyl-2-
propanone.
The effect of varying the amount of zinc on the yield of l-phenyl-2-propanone was
studied. A solution of l-phenyl-2-nitropropene in acetic acid was heated to 100° C
with one, two, three and four equivalents of zinc powder. Analysis by G C - M S
indicated an increasing proportion of zinc resulted in a greater rate of l-phenyl-2-
propanone production.
3.3.2. Other metals
The reduction of l-phenyl-2-nitropropene using Raney nickel and sodium
hypophosphite (Scheme 6), iron metal and hydrochloric acid (Scheme 7) and zinc metal
in acetic acid (Scheme 8) have been documented in the literature.7"8"9 It was of some
interest to determine if metals other than zinc could be used in the reaction under study.
If so, it could provide an alert to monitor diversion of these metals from legitimate
sources.
Equimolar amounts of tin (granulated), aluminium (powder), iron (filings), and zinc
(granulated, activated with copper) and 1-phenyl-nitropropene were combined in
glacial acetic acid and were heated to (100-105° C) for 2 hours. The yield of these
reactions was not determined, however the rate of formation of the desired product was
monitored by G C - M S .
Table 2. Substitution metals
Substitution Metal
Tin (granulated)
Aluminium (powder)
Iron (filings)
Zinc (granulated)
Reaction with Nitrostyrene to give l-Phenyl-2-propanone
Desired product obtained - reaction incomplete
N o Reaction
Desired product obtained - reaction incomplete
Small amount of product
Al, Zn, Fe, Sn, Zn(Pwdr).
Increasing efficiency
22
l-Phenyl-2-propanone was detected by G C - M S in the reaction using tin, iron or
granulated zinc. In the reaction using aluminium metal, only starting material was
observed by G C - M S . Tin and iron can be used to substitute for zinc metal, however
zinc powder was determined to be the most efficient metal in the reduction of 1-phenyl-
2-nitropropene to l-phenyl-2-propanone. Iron filings, granulated zinc and tin, due to
their physical characteristics for example a lack of surface area, did not have the same
reactivity as zinc metal in the powdered form. A study of the reactivity of the
powdered form of these metals is of some interest, however time constraints precluded
an investigation in the present work. However, in respect to the availability of these
materials to clandestine laboratories, tin and iron offer two possible substitutes for zinc.
Table 3: Standard Reduction Potentials
Reaction
2H + + 2e"±+ H 2
Al+3+3e £» Al
Zn+ 2 +2e" ±5 Zn
Fe + z+2e"^Fe
Sn+2 +2e" ±+ Sn
Potential (volts)
0.0000
-1.706
-0.7628
-0.409
-0.1364
Source: CRC. Handbook of Chemistry and Physics.
Sn,Fe, Zn, Al
Increasing reduction potential
The standard reduction potentials for these metals indicate aluminium would be the
most reactive metal with acetic acid, followed by zinc, iron and tin. However
aluminium has a thin film of the protective oxide and would not react under acidic
conditions. Under experimental conditions the metals in a granulated form did not have
the same reactivity as zinc metal in the powdered form.
23
3.3.3 T w o phase solvent system
l-Phenyl-2-nitropropene can be converted to l-phenyl-2-propanone with iron and
hydrochloric acid in the presence of ferric chloride and a two-phase solvent system
(toluene/water) as reported in scheme 9. This method gave a yellow oil (53%),
containing l-phenyl-2-nitropropene (31%), l-phenyl-2-propanone (11%) and the
intermediate l-phenyl-2-propanone oxime (ketoxime; Scheme 8) (1%). Monitoring by
G C - M S indicated that the reaction in a toluene two-phase mixture is slower compared
to that using acetic acid.
3.3.4 Reactivity of l-phenyl-2-propanone
The reactivity of l-phenyl-2-propanone in the presence of zinc and acetic acid was
examined by combining the three reactants and heating to reflux for 1 hr. Analysis by
G C - M S showed that no new compounds were formed, indicating that l-phenyl-2-
propanone does not react in the presence of zinc and acetic acid.
3.3.5 Varying the combination of reagents
Adding a solution of l-phenyl-2-nitropropene in acetic acid to a suspension of zinc
powder in acetic acid, refluxing for 12 hours yielded unreacted nitrostyrene. In further
experiments a solution of l-phenyl-2-nitropropene was added down the condenser to a
refluxing solution of zinc in acetic acid the reaction was refluxed for 2 hr. Analysis by
G C - M S indicated the major component was starting material. W h e n the reaction time
was increased to 4 hours the yield of P2P from this reaction was 11 % (determined by
GC-FID).
3.3.6 Extraction with toluene
Toluene is more readily available than dichloromethane and is a c o m m o n material
found at clandestine laboratories where it is used as an extraction solvent.
The reactions described in the previous section were repeated, but the product was
recovered by extraction with toluene, yields of 27-32% were obtained (determined by
GC-FID).
24
3.3.7 Synthesis of l-Phenyl-2-propanone and purification:
Various methods were used to purify samples of the ketone obtained from reactions
similar to those described above. Vacuum distillation afforded a yield of 4 3 % , silica gel
chromatography 2 6 % and steam distillation 51%. The spectral data, ! H - N M R (Fig. 2
appendix), were consistent with those of l-phenyl-2-propanone.
3.3.8 Clandestine method (Experiment based on handwritten notes)
The method described in a 'recipe' involved refluxing l-phenyl-2-nitropropene with
2.5 equivalents of zinc powder in 9 0 % acetic acid for one hour and steam distillation of
the product.
In a 20L stainless steel container add 250g of zinc to 2L of acetic acid and 200 mL of
distilled water. The zinc is allowed to react and 250g of 1 -phenyl-2-nitropropene is
added. The mixture is refluxedfor one hour. Water is added, approximately 17 to 18 L.
The apparatus is then changed to a distillation setup and the mixture is brought to the
boil (180 °C) then turned down (150 °C). The distillate should appear at a rate of two
drips per second, minimum, if not the heat is turned up. Distillation occurs for eight
hours to fill a 20L bucket. Washing soda (sodium carbonate) is added. The distillate is
split into two 10L lots. The product l-phenyl-2- propanone (P2P) appears as a yellow
liquid at the top and a tap located at the bottom of the 10L bucket is used to drain the
water layer.
The experimental procedure reported above was replicated on one hundredth of the
scale. After steam distillation the distillate was extracted with toluene (because of the
small scale of the reaction) to give l-phenyl-2-propanone in 3 9 % yield.
The reaction was monitored by G C - M S and was essentially complete after 1 hour.
The differences to the laboratory experiments was the order in which the materials were
combined, the concentration of acetic acid (98% to 90%) and the number of zinc
equivalents used (5 eq to 2.5 eq).
25
The isolation of l-phenyl-2-propanone using the clandestine method of steam
distillation eliminates the need for a number of items; solvents (toluene) used in
extraction, drying agents and methods used to evaporate solvents. The use of a bucket
with a tap at the bottom serves effectively as a normal separatory funnel.
The experiment when repeated using 5 equivalents of zinc, gave a satisfactory yield of
l-phenyl-2-propanone (53%) that was considerably higher in purity (GC-MS)
compared to that isolated by a toluene extraction.
3.3.9 One-pot conversion of benzaldehyde to l-phenvl-2-propanone
Scheme 12
O
H 1. EtNO-yAcOH
* N ^ > 2. Zn/AcOH ^ " > ^
Benzaldehyde, nitroethane and ammonium carbonate were added in the molar ratio
1.5:1:0.1 to acetic acid and the mixture refluxed for 1 hr. Five equivalents of zinc in
acetic acid were added portionwise to the cooled solution and the mixture was refluxed
for 1 hr. Work-up, by extraction with dichloromethane, afforded the product in 8 7 %
recovery. Vacuum distillation of the crude product afforded l-phenyl-2-propanone in a
4 4 % yield.
The reaction was monitored by GC-MS and was essentially complete after thirty
minutes from the addition of zinc. Following the manufacture of l-phenyl-2-
nitropropene in situ, zinc powder and acetic acid can be added to the reaction mixture
without prior separation and purification of the nitropropene.
26
3.4. Determination of P2P in Clandestine reaction mixtures
A method was developed for the quantitation of l-phenyl-2-propanone (P2P) and
N-formylamphetamine in clandestine reaction mixtures using gas chromatography
flame ionisation. The principal objective of this part of the study was to develop a
simple, fast, and efficient method for the quantitation of P2P in reaction mixtures.
A number of compounds were investigated as possible internal standards.
Propiophenone, initially chosen because of its similar chemical characteristics
(molecular weight and boiling point) to l-phenyl-2-propanone, had Rt 7.13 which was
close to that of P2P (Rt 6.79). Acetophenone, Rt 6.41 and possessing similar chemical
properties, was found to be suitable. Ethyl acetate was used as the solvent.
Calibration curves of l-phenyl-2-propanone and N-formylamphetamine.
AreaRate-
8-
6-
4-•
2-
0-i
2 / ^ \ y y ^
i 0I2 0.4 o'.e Amwit RiMo
P2P at exp. RT: 6.922 FID1 A, Correlation: 0 Residual Std. Dev.: 0 Formula: y » rax + b
m: 14.01573 b: 1.80067e-l x: Amount Ratio y: Area Ratio
,99777 .28855
AraaRatloj
H J
12-;
10'-"
8-i
*:. 4-;
2-
<
2
\S^
I)
3 / ^
Amount Riftn 1
Formylamphetamine at exp. RT: 9.642 FID1 A, Correlation: 0.99976 Residual Std. Dev.: 0.17287 Formula: y - mx + b
m: 8.31835 b: -8.07315e-3 x: Amount Ratio y: Area Ratio
27
The determination of the concentration of l-phenyl-2-propanone was done using a four
point calibration curve, measuring the ratio of the absolute peak area response of P2P to
the absolute peak area of the internal standard acetophenone. The response was found
to be linear in the concentration ranges studied with a correlation coefficient of 0.99777
for P2P. A similar technique was used for the determination of
N-formylamphetamine in crude reaction mixtures (see Chapter 4). The response was
also found to be linear with a correlation coefficient of 0.99976.
3.5. Conclusion
Reduction of l-phenyl-2-nitropropene using zinc powder in glacial acetic acid was
found to afford l-phenyl-2-propanone in a reasonable yield. The maximum yield for
this reaction was achieved using 5 equivalents of zinc powder for each mole of
l-phenyl-2-nitropropene. The procedure was to add zinc powder portionwise to a
solution of the nitroalkene in glacial acetic acid followed by heating at reflux for 1-2 hr.
However, G C - M S analysis showed that the maximum yield was achieved after thirty
minutes. The ketoxime, l-phenyl-2-propanone oxime, was also detected in the reaction
mixture by G C - M S , however this intermediate was eventually converted to the ketone
under the reaction conditions.
Substitution of zinc with tin and iron also resulted in the formation of l-phenyl-2-
propanone. Their reactivity was lower than that of zinc because the metals were not in
a powdered form. Aluminium powder was unreactive under these conditions. Zinc
powder was determined to be the most efficient metal in the reduction of l-phenyl-2-
nitropropene.
l-Phenyl-2-propanone is unreactive in the presence of zinc and acetic acid and
therefore, there should be no loss of product thorough side reactions.
The use of zinc in other solvent systems such as toluene/hydrochloric acid was
investigated. l-Phenyl-2-nitropropene in the presence of zinc, toluene and
hydrochloric acid and heated at reflux for 1 hour gave an incomplete reaction. Analysis
by G C - M S indicated that the intermediate oxime and l-phenyl-2-propanone were
produced.
28
Variations in the order of addition of reactants produced a lower yield and/or a longer
reaction time. Extraction of the product using different techniques was also
investigated. Basifying the acidic reaction medium followed by extraction with
dichloromethane resulted in the formation of emulsions. Using toluene to extract a
diluted reaction mixture was more successful.
Purification of the crude reaction product by steam distillation directly from the
reaction mixture, or vacuum distillation following solvent extraction gave satisfactory
yields ( 5 3 % and 4 3 % respectively). Both purification techniques give a product, which
is pure when analysed by ] H - N M R and G C - M S . Clandestine operators as indicated by
seized 'recipes', prefer steam distillation because of its simplicity.
The clandestine method used a zinc to nitroalkene ratio of 2.5:1 in 90% acetic acid and
refluxing for 1 hr. The product recovered by steam distillation was obtained in 3 9 %
yield.
It is also possible to manufacture l-phenyl-2-propanone from benzaldehyde and
nitroethane without prior separation and purification of 1 -phenyl-2-nitropropene. The
addition of zinc powder after the condensation reaction gave a red oil (87%) which, on
vacuum distillation, afforded the ketone in 4 4 % yield, with respect to the nitroethane.
The general method described is a departure from the methods of reducing l-phenyl-2-
nitropropene that are commonly found at clandestine laboratories. It requires no
knowledge of chemistry, it offers little chance of failure, produces satisfactory yields,
does not require expensive chemical apparatus or glassware, and uses currently
available (and easily synthesised) precursors. The most significant feature is the use of
zinc, which is widely available from a number of commercial sources. It is important
for enforcement personnel to be aware of the three major reagents in this method (zinc
metal, acetic acid and l-phenyl-2-nitropropene) for intelligence gathering purposes and
for their safety in assessing and seizing such a laboratory.
29
3.6. References
1. Forbes, I. J. and Kirkbride, K. P., "The Origin of Alkenes in Illicit
Amphetamine: An Examination of the Illicit Synthesis of Phenyl-2-Propanone",
Journal of Forensic Sciences, JFSCA, 1992,37(5), 1311-1318.
2. Tsutsumi, M. " An Illegal Preparation of Amphetamine-Like compound",
Science and Crime Detection (Japan), 1953, 6, 650-52.
3. Herbst, R.M. and Manske, R.H., "A Methyl Benzyl Ketone from Phenylacetic
and Acetic Acids", Organic Syntheses, Collective Volume II, 1943, 389-391.
4. King, J.A. and McMillan, F.H., "The Decarboxylative Acylation of Arylacetic
Acids", Journal of the American Chemical Society, 1951, 73, 4911-4915.
5. Julian, P.L. and Oliver, J.J., "B. Methyl Benzyl Ketone from alpha-
Phenylacetoacetonitrile", Organic Syntheses, Collective Volume II, 1943, 391-
392.
6. Mason, J.P. and Terry, L.I., " Preparation of Phenylacetone", Journal of the
American Chemical Society, 1940, 62, 1622.
7. Monti, D., Gramatica, P., Speranza, G. and Manitto, P., "Reaction of
Nitroolefins with Raney Nickel and Sodium Hypophosphite, a Mild Method for
Converting Nitroolefins into Ketones (or Aldehydes)", Tetrahedron Letters,
1983, 24 (4), 417-418.
8. Hass, H.B., Susie, A.G. and Heider, R.L., "Nitro Alkene Derivatives", Journal
of Organic Chemistry, 1950,15, 8-14.
9. Nightingale, D. and Janes, J.R., "The Preparation of Ketones from
Nitroolefins", Journal American Chemical Society, 1944, 66, 352.
30
10. Saikia, A.K., Barua, N.C., Sharma, R.P., and Ghosh, A.C., "The Zinc-
Trifluoroacetic Acid in Organic Solvents: A Facile Procedure for the
Conversion of Nitroolefins into Carbonyl Compounds under Mild Conditions",
Journal of Chemical Research (S), 1996, 124-125.
11. Ballini, R and Bosica, G., "Chemoselective Conversion of Conjugated
Nitroalkanes into Ketones by Sodium Borohydride-Hydrogen Peroxide: A N e w
synthesis of 4-Oxoalkanoic Acids, Dihydrojasmone and exo-Brevicomin",
Synthesis, 1994, 723-726.
12. Allen, A.C., Stevenson, M.L., Nakamura, S.M. and Ely, R.A., "Differentiation
of Illicit Phenyl-2-Propanone Synthesized from Phenylacetic Acid with Acetic
Anhydride Versus Lead (II) Acetate", Journal of Forensic Sciences, JFSCA,
1992,37(1), 301-322.
31
Chapter Four
4. Syntheses of N-formylamphetamine
The reductive amination of carbonyl compounds to the corresponding amines by
reaction with excess ammonium formate (Leuckart reaction) is a very useful procedure
for the preparation of N-formyl derivatives of amines.1 The Leuckart method of
amphetamine production may be considered as a three-step reaction consisting of:
1. A formylation stage: the condensation of l-phenyl-2-propanone with
formamide in the presence of formic acid.
2. A hydrolysis step: hydrolysis of the N-formylamphetamine intermediate with
hydrochloric acid.
3. A purification step: extraction of amphetamine and precipitation as the
hydrochloride, followed by washing and/or recrystallisation of the product.
Scheme 1. The Leuckart Reaction
R R R \ - ^ \ H + \ M M
)=0 + NH4+HC02 *• V—NHCHO /— NH,
R R R
The most effective reagent in the Leuckart reaction appears to be ammonium formate
or formamide, supplemented by the addition of sufficient 9 0 % formic acid to maintain
a slightly acidic medium and serve as an active reducing agent. It has been reported1
that the ketone and ammonium formate or formamide are usually employed in a
molecular ratio of 1:4 or 1:5. Crossley and Moore found that the addition of formic acid
to formamide increased the yield in comparison to formamide alone. One to three
equivalents of formic acid is generally required. Occasionally, distillation of
accumulated water may be necessary to maintain a suitably high reaction temperature.
32
Scheme 2
^ ^ ^ O H NK
1-Phenyl-2-propanone Formamide
HCO,H
N-formylamphetamine
N-formylamphetamine has been produced when l-phenyl-2-propanone was allowed to
react with formamide and formic acid in a molar ratio of 1:4:0.32 under Dean-Stark
conditions. Five equivalents of formic acid were added during the course of the
reaction.2 However no yield for the reaction was given (Scheme 2).
Scheme 3
HCOoNH,
^ ^ Heat 130-160 oC 3 hrs
1 -Phenyl-2-propanone
r H
N-Formylamphetamine
HCI reflux
^ ^ N H 2
Amphetamine
Amphetamine has been synthesised from l-phenyl-2-propanone via
N-formylamphetamine using ammonium formate.3 l-Phenyl-2-propanone and
ammonium formate, in the molar ratio of 1:3 were combined and heated (160-180° C)
for 3 hours. The contents of the distillation flask were then cooled and hydrolysed by
heating with concentrated hydrochloric acid for 3 hours. The reaction mixture was
washed with benzene (to remove unreacted ketone), made alkaline, and steam distilled.
The distillate was extracted with benzene and the product distilled to afford l-phenyl-2-
aminopropane (amphetamine) 4 1 % yield (Scheme 3).
33
Scheme 4
(NH4)2C03 +2 HC02H
Ammonium carbonate Formic acid
2 NH4C02H +C02 +H20
Ammonium formate
NH4C02H Ammonium formate
HCONH2 +H20 Formamide
A m m o n i u m formate is well documented as a reducing agent in the literature 4'5'6.
Ammonium carbonate and formic acid generate ammonium formate in situ, which in
turn can dehydrate to furnish formamide (Scheme 4). This can react with the carbonyl
group of l-phenyl-2-propanone to form the corresponding imine, which can be reduced
by formic acid, formamide and/or ammonium formate1 to form the N-formyl derivative
of the corresponding amine (Scheme 5).
Carbonyl Formamide
Scheme 5
O
^ ° +H2N^H ^ 1ST ^H + H20
Imine
Reducing agent
Formyl derivative
4.1. Western Australian method
Chemicals and 'recipes' seized from several clandestine amphetamine laboratories
suggested that N-formylamphetamine was prepared from the reaction of l-phenyl-2-
propanone (P2P), ammonium carbonate and formic acid (Scheme 6). Ammonium
carbonate and formic acid form ammonium formate as described in Scheme 5. The use
of ammonium carbonate in both the first reaction (see Chapter 2) and third reaction in
34
the sequence is quite innovative and reduces the total number of chemicals needed for
the synthesis of amphetamine from benzaldehyde. Once again clandestine operators
were using 'homemade' equipment, condensers and reaction vessels, in this step.
Scheme 6
^ ^
1 -Phenyl-2-propanone
(NH4)2CO; 2"-"~"3
HCOoH
N-Formylamphetamine
4.2. Results and Discussion
A number of reactions using commercial grade and impure l-phenyl-2-propanone
(P2P) were attempted. All reactions were carried out at a temperature of 160° C, using a
ratio of 5 moles of Leuckart reagent to 1 mole of the ketone.1
4.2.1. Commercial grade l-phenyl-2-propanone
The initial experiments were carried out using commercial grade l-phenyl-2-
propanone. The time required for the reaction, typical yields using formamide as the
Leuckart reagent, the effect of using excess formic acid and whether it was necessary to
remove water generated in the reaction were examined.
4.2.2. Reaction with formamide
l-Phenyl-2-propanone and five equivalents of formamide were heated under reflux and
the reaction was monitored by G C - M S . After 7.5 hr, the major component was
l-phenyl-2-propanone and N-formylamphetamine was the minor component. After
12 hours, the reaction was essentially complete and work-up afforded the product in
5 9 % yield.
35
Table 1: Leuckart reactions using commercial P2P
Leuckart reagent
Formamide (5 eq)
Formamide (5 eq)
Formic acid (1 eq)
Ammonium carbonate (5 eq)
Formic acid (5 eq)
Ammonium carbonate (5 eq)
Formic acid (excess)
Distillation of Water
Ammonium carbonate (5 eq)
Formic acid (excess)
Time of Reaction (Hours)
12
4
8
11
24
Yield (%)
59
71 to 99
50
50
78
4.2.3. Reaction with formamide and formic acid
l-Phenyl-2-propanone, five equivalents of formamide and one equivalent of formic
acid were refluxed at 160° C for four hours. G C - M S monitoring of the reaction
indicated that the reaction was complete after 1.5 hr. Work-up afforded the crude
product (89%). The oil was washed with hexane to yield a light brown oil (71%) which
appeared essentially pure when analysed by G C - M S FT-TR and [ H - N M R spectroscopy
(Fig. 3 and 7, appendix).
The proton NMR spectrum showed that the compound existed as a mixture of the Z-
and E- rotamers in 78 and 2 2 % respectively. Separate signals were observed for the
secondary methyl group at 8 1.12 (d, J = 7 Hz) (Z) and 8 1.23 (d, J = 7 Hz) (E), the
methine proton group at 8 4.28 (dq, J = 7 Hz) and 8 3.61 (dq, J = 7 Hz) (£), and the
formyl proton at 8 7.95 (br s) (Z) and 8 7.64 (d, J = 11 Hz) (£) which showed
coupling to the -N-H at 8 6.68 7.
36
4.2.4. Reaction with ammonium formate
Using five molar equivalents of ammonium carbonate and formic acid and heating
under reflux for 8 hr gave a 5 0 % yield of N-formylamphetamine.
4.2.5. Reaction with ammonium formate in excess formic acid
The reaction was repeated using excess formic acid and heating for eight hours. The
water was removed by distillation, then the reaction mixture was heated for an
additional 3 hr to give N-formylamphetamine in a 5 0 % yield. A similar experiment in
which water was not removed afforded N-formylamphetamine in 7 8 % yield. Some
l-phenyl-2-propanone was observed to co-distill with the water in the first reaction,
which may explain the reduced yield. In the second reaction condensation of water was
observed in the condenser, effectively removing water from the reaction mixture,
driving the formation of formamide.
4.2.6. Procedure used in clandestine laboratory
T w o recipes seized from two separate clandestine laboratories indicated that the
operators were making ammonium formate in situ. The water generated from this
reaction was distilled and the co-distilled l-phenyl-2-propanone was returned to the
reaction vessel.
This process was repeated in the laboratory. After 8 hours of refluxing, water was
removed by distillation. The reaction was further refluxed for 3 hours to give a 5 0 %
yield of N-formylamphetamine. W h e n this reaction was repeated using ammonium
carbonate and an excess of formic acid without the distillation of water, the reaction
was complete after 24 hours. Although the time required was considerably greater, the
yield increased to 7 8 % .
A well-known underground publication8 describes a variation of the Leuckart reaction.
N-formylamphetamine can be prepared by the reaction of P2P with formamide, it is
suggested that the two compounds should be combined in a molecular ratio of 1:2 and
left to stand at room temperature for approximately one week. A catalytic amount of
formic acid is then added and the mixture heated to 160-165° C for one hour.
A m m o n i u m formate is also mentioned as a suitable reagent.
37
4.2.7. Impure l-phenyl-2-propanone
The homemade equipment typically found at these clandestine laboratories is not ideal
for a vacuum distillation of l-phenyl-2-propanone, although steam distillation has been
described in certain seized 'recipes'. This tends to suggest that impure P2P may be used
directly in this step.
The experiments in this section were carried out using impure l-phenyl-2-propanone
synthesised from l-phenyl-2-nitropropene and five equivalents of zinc in acetic acid.
The yields of N-formylamphetamine (determined by GC-FID) are based on the starting
material consisting of 3 2 % l-phenyl-2-propanone (determined by GC-FID).
Table 2: Leuckart reactions using impure P2P
Leuckart reagent
Formamide (5 eq)
Formamide (5 eq)
Formic acid (1 eq)
Ammonium carbonate (5 eq)
Formic acid (5 eq)
Ammonium carbonate (5 eq)
Excess formic acid
Time of Reaction (Hours)
11
3
14
24
Yield (%) based
on 32% P2P
39
19
86
78
4.2.8. Reaction with formamide
l-Phenyl-2-propanone and five equivalents of formamide were heated under reflux for
11 hours to give a 3 9 % yield of N-formylamphetamine
4.2.9. Reaction with formamide and formic acid
This reaction was repeated using the same reagents and one molar equivalent of formic
acid. The reactants were heated at reflux for three hours to give a 1 9 % yield of
N-formylamphetamine. G C - M S monitoring of the reaction indicated that the reaction
was complete in 1 hr.
38
4.2.10. Reaction with ammonium formate
l-Phenyl-2-propanone and five equivalents of both formic acid and ammonium
carbonate were heated under reflux for 14 hours to give a yield of 86%.
4.2.11. Reaction with ammonium formate/excess formic acid
This reaction was repeated using an excess of formic acid. The reactants were heated to
reflux for 4 days (6 hours a day) to give a yield of 78%.
The results indicate crude P2P can be converted to N-formylamphetamine with
ammonium formate in excellent yield.
Table 3: Summary of main reactions
Leuckart reagent
Formamide (5 eq)
Formamide (5 eq) +
Formic acid (1 eq)
Ammonium carbonate (5 eq)
Formic acid (5 eq)
Ammonium carbonate (5 eq)
Excess formic acid
l-Phenyl-2-propanone
(Yield %)
Commercial
59
89-99
50
78
Impure
39
19
86
78
The yield of product from the experiments using impure P2P and ammonium formate
as the Leuckart reagent was very high (86%), compared to 5 0 % using commercial P2P.
Reaction of commercial and impure P2P with ammonium formate in excess formic acid
gave similar yields (78%), based on the purity of P2P. All reactions were conducted on
a small scale which could explain the variation in yield, also the products may contain
traces of acid (acetic) from the previous steps or high molecular weight compounds
from side reaction resulting from impure starting material.
39
4.3. Conclusion
The reaction of l-phenyl-2-propanone, ammonium carbonate and formic acid was
found to produce N-formylamphetamine. Commercial P2P was used initially to find
the optimal reaction conditions. The ketone and ammonium formate or formamide were
employed in a molecular ratio of 1:5. Reactions using formamide as the Leuckart
reagent also included 1 equivalent of formic acid. A large excess of formic acid was
added when ammonium carbonate was used.
The reaction of commercial 1-phenyl-2-propanone with formamide supplemented with
one equivalent of formic acid increased the yield from 5 9 % to 7 1 % , in a shorter
reaction time (12 hr to 4 hr). Using ammonium formate with an excess of formic acid
also improved the yield (50 % to 78%), however this lengthened the reaction time by
12 hr. Removal of water by distillation did not improve the yield (50%), but it reduced
the reaction time by half (24 hr to 11 hr).
It was unclear whether illicit operators were purifying the 'homemade' P2P. Therefore
the yields for the reaction of impure P2P with formamide and ammonium formate were
determined. The reaction with formamide gave a satisfactory yield (39%). The
addition of formic acid did not improve the yield (19%). The reaction of ammonium
formate gave a high yield (86%), adding an excess of formic acid did not improve the
yield (78%) and lengthened the reaction time by 10 hours. This result suggests only a
catalytic amount of formic acid is required, and an excess of formic acid may interfere
with the reaction.
Purification of P2P by distillation would not appear to be essential. Even using impure
P2P and ammonium formate the conversions were very high. Operators may not be
worried about the yield of these reactions because of the large scaling options present
in the initial reactions.
40
These results indicate that ammonium carbonate has a wide applicability being used as
a nitrogen source in the Leuckart reaction and previously as a catalyst to produce 1-
phenyl-2-nitropropene. Substitution of ammonium formate for formamide as the
Leuckart reagent was found to give N-formylamphetamine in good yields (50 to 78%).
4.4. References
1. Crossley, F. S. and Moore, M. L., " Studies on the Leuckart Reaction", Journal
of Organic Chemistry, 1944, 9, 529-536.
2. Sanger, D. G, Humphreys, I. J., Patel, A. C, Japp, M., Osborne, R. G. L., "The
significance of gas chromatographic impurity patterns obtained from illicitly
produced amphetamine", Forensic Science International, 1985, 28, 7-17.
3. Cervinka, O., Kroupova, E., and Belovsky, O., "Asymmetric reactions. XXDC
Absolute configuration of co-Phenyl-2-alkylamines and Their N-Methyl
Derivatives", Collection of Czechoslovak Chemical Communications, Chemical
Abstract 70:37323d (1969).
4. Terpko, M.O., and Heck, R.F., "Palladium-Catalyzed Triethylammonium
Formate Reductions. Selective Reduction of Dinitroaromatic Compounds",
Journal of Organic Chemistry, 1980, 45, 4992-4993.
5. Ram, S. and Ehrenkaufer, R. E., "Ammonium Formate in Organic Synthesis: A
versatile Agent in Catalytic Hydrogen Transfer Reductions", Synthesis, 1988,
91-95.
6. Ram, S. and Ehrenkaufer, R. E., "A General Procedure for Mild and Rapid
Reduction of Aliphatic and Aromatic Nitro Compounds using Ammonium
Formate as a Catalytic Hydrogen Transfer Agent", Tetrahedron Letters, 1984,
25 (32), 3415-3418.
41
7. Enders, D., Haertwig, A., Raabe, G., Runsink, J., "Diastero- and
Enantioselective Synthesis of Vicinal Amino Alcohols by Oxa Michael
Addition of N-Formylnorephedrine to Nitro Alkenes", European Journal of
Chemistry, 1998, 1771-1792.
8. Uncle Fester Secrets of Methamphetamine Manufacture. 4th Ed, Loompanics
Unlimited (Washington).
42
Chapter Five
5. Syntheses of Amphetamine
A number of different chemical methods for the manufacture of amphetamine have
been published.1 Some are relatively straight forward and require only crude makeshift
processes, others use sophisticated technology and a number of advanced chemical
procedures. The manufacturing process selected is determined by a number of factors,
including the availability of chemical precursors and the expertise of the operator.
l-Phenyl-2-propanone is a precursor in the manufacture of amphetamine and
methylamphetamine. Most clandestine laboratories in Australia manufacture
methylamphetamine by the reduction of ephedrine/pseudoephedrine using a number of
different synthetic routes. However the clandestine amphetamine laboratories seized
appear to favour the reductive amination of l-phenyl-2-propanone, often by the
Leuckart route.
Scheme 1: Reductive animation of l-Phenyl-2-propanone
Reduction
^ ^ U ^ ^ NHR
1-Phenyl-2-propanone R = H , Amphetamine R=CH3, Methylaminetamine
The manufacturing techniques commonly encountered in clandestine amphetamine
laboratories are listed below.
• Reduction of l-phenyl-2-nitropropene to amphetamine.2'3,4
• Reductive amination of 1 -phenyl-2-propanone using a Leuckart reagent.
• Reductive amination of l-phenyl-2-propanone using Al, N H 4 O H and H g amalgam.
• Reduction of l-phenyl-2-propanone oxime using a N a amalgam.
43
Scheme 2
1 -Phenyl-2-nitropropene
'2 1. H2S04, Hg cathode, Pb anode, 4amps, 30-40°C, 20hrs. _ »
OR 2. AcOH, MeOH, Raney Ni, 1000 psi H2, 40-1 OOoC, 3hrs. OR 3. MeOH, Raney Ni, 50-80 atm H2, 20-50oC.
^ ^
Amphetamine
Condensation of benzaldehyde with nitroethane yields l-phenyl-2-nitropropene as
described in Chapter 2. The precursor 1-phenyl-2-nitropropene may be converted
directly to amphetamine under reducing conditions (Scheme 2).1 Electrolytic reduction,
using sulphuric acid and a mercury cathode and lead anode, has been reported to give a
2 0 % yield of amphetamine.2 Catalytic reduction of nitrostyrene using a Raney Ni
catalyst in an acidic solvent (reaction 2)3 and in methanol (reaction 3)4 under elevated
pressure gave amphetamine in yields of 60 and 6 1 % respectively.
Scheme 3
(NH4)2COa
^ ^ ^ HCO,H
1 -Phenyl-2-propanone
" ^ H N r>
H N-formylamphetamine
cone. HCI
^V^
Amphetamine
A variety of methods for the preparation l-phenyl-2-propanone have been documented
in the literature. These methods, and the preparation of l-phenyl-2-propanone from
l-phenyl-2-nitropropene using Zn-AcOH are described in Chapter 3. l-Phenyl-2-
propanone can be converted to N-formylamphetamine using the Leuckart reagent
ammonium formate5 as described in Chapter 4. N-formylamphetamine is readily
hydrolysed with concentrated hydrochloric acid to give amphetamine (Scheme 3).
44
Scheme 4
+ NH4OH Al grit, HgCI2, EtOH
^ ^ ^ * < ^
1 -Phenyl-2-propanone Ammonium hydroxide Amphetamine
Amphetamine can be obtained in a 3 0 % yield in a one step synthesis by heating to
reflux a mixture of l-phenyl-2-propanone, ethanol, ammonium hydroxide, aluminium
grit and a catalytic amount of mercuric chloride (Scheme 4).6
Scheme 5
+ :NH2OH EtOH, NaOH
1 -phenyl-2-propanone Hydroxylamine *OH
1 -Phenyl-2-propanone-oxime
AcOH 3 % sodium amalgam
^ ^
Amphetamine has also been prepared by the reduction of the intermediate l-phenyl-2-
propanone oxime by means of a sodium amalgam in dilute acetic acid (Scheme 5),
however yields were not reported for this method.7 The oxime is generated upon
reaction of l-phenyl-2-propanone with hydroxylamine.
45
5.1. Results and Discussion
The N-formylamphetamine used in this step of the Leuckart reaction was prepared
from l-phenyl-2-propanone, ammonium carbonate and formic acid (Scheme 3).
N-formylamphetamine and hydrochloric acid were heated to reflux for 2 hours to form
the free base. Following extraction into toluene, HCI gas was used to form the
hydrochloride salt (0.6 g). Washing this product with acetone gave amphetamine in a
3 7 % yield. The spectral data, ̂ - N M R , FT-IR (Fig. 4 and 8, appendix), and melting
point were consistent with those of 2-amino-l-phenylpropane (amphetamine).
5.2. Conclusion
The final step in the Leuckart reaction of the hydrolysis of N-formylamphetamine was
found to give the product 2-amino-l-phenylpropane hydrochloride (amphetamine) in a
3 7 % yield.
5.3. References
1. Allen, A. and Cantrell, T.S., "Synthetic Reductions in Clandestine
Amphetamine and Methamphetamine Laboratories: A review", Forensic
Science International, 1989,42, 183-199.
2. Alles, G.A., "d,/-yBeta-Phenylisopropylamines", Journal of the American
Chemical Society, 1932, 54, 271-274.
3. Tindall, J.B., "Reduction of Nitroolefins", United States Patent, #2636901,
April 28, 1953.
Chemical Abstract 48:277If (1954).
4. Stochdorph, G. and von Schickh, O., "Saturated amines", German patent, #
848197, September 1, 1952.
Chemical Abstract 47:5438a (1953).
46
Crossley, F. S. and Moore, M. L., " Studies on the Leuckart Reaction", Journal
of Organic Chemistry, 1944, 9, 529-536.
Wassink, B.H.G., Duijndam, A., Jansen, A.C.A, "A Synthesis of
Amphetamine", Journal of Chemical Education, 1974, 51, 671.
Hey, H.H., "d,l-p-Phenylisopropylamine and Related Compounds", Journal of
the Chemical Society, 1930, 18-21.
47
Chapter Six
6. Summary - Synthesis of amphetamine from benzaldehyde
The study presented shows a novel application of the conversion of benzaldehyde to
amphetamine using ammonium carbonate and zinc (Scheme 1). The chemicals and
apparatus seized from several clandestine laboratories indicated the illicit process was
being carried out at up to a kilogram in scale batches, using 'homemade' equipment.
The aim of this project was to identify the synthetic process that was used in the
preparation of amphetamine from benzaldehyde and to determine the possible yield.
Scheme 1
H + CH3CH2NO
Benzaldehyde Nitroethane
(NH4)2CQ3
AcOH ^ ^ CH3
1 -Phenyl-2-nitropropene
Zinc AcOH
(NH4)2C03
^ ^ o HN^^O HCO2H
u N-formylamphetamine 1 -Phenyl-2-propanone
The scheme above shows the synthetic route that was being employed to manufacture
amphetamine. In the initial step benzaldehyde and nitroethane were condensed using
ammonium carbonate in acetic acid as the catalyst. The best yield for this reaction was
achieved using benzaldehyde, nitroethane and ammonium carbonate in the molar ratio
1.5:1:0.25 and heating under reflux for 6 hr. This reaction gave l-phenyl-2-
nitropropene in a yield of 5 4 % with respect to the nitroethane.
48
The second reaction used zinc powder in acetic acid to reduce l-phenyl-2-nitropropene
to the ketone (l-phenyl-2-propanone). The nitrostyrene and zinc powder are combined
in a molecular ratio of 1:5 and heated under reflux for 2 hr. Following this reaction,
steam distillation gave l-phenyl-2-propanone in a 5 3 % yield.
Tin and iron were found to be useful metals in the substitution of zinc. However zinc
powder was determined to be the most efficient metal in the reduction of l-phenyl-2-
nitropropene to l-phenyl-2-propanone. Further investigation of the substitution of these
metals for zinc would be of interest.
l-Phenyl-2-propanone can also be synthesised in a one-pot reaction following the
manufacture of l-phenyl-2-nitropropene in situ. Zinc powder and acetic acid can be
added to the reaction mixture without prior separation and purification of the
nitropropene. l-Phenyl-2-propanone was obtained following distillation of the crude
product in a 4 4 % yield.
Ammonium carbonate is also used as a source of nitrogen, in the reductive amination of
l-phenyl-2-propanone to give N-formylamphetamine. The use of ammonium
carbonate in both the first reaction (preparation of l-phenyl-2-nitropropene) and third
reaction, reduces the total number of chemicals needed for the synthesis of
amphetamine from benzaldehyde. W h e n ammonium carbonate is combined with
formic acid, ammonium formate is generated, a common Leuckart reagent used for the
conversion of ketones to their formyl derivatives.
Reacting commercial l-phenyl-2-propanone with stoichiometric amounts of
ammonium carbonate and formic acid gave N-formylamphetamine in a yield of 50%.
The use of excess formic acid increased the yield (78%), however lengthened the
reaction time by 10 hours. Using impure P2P and ammonium formate as the Leuckart
reagent the yield was determined to be between 78-86% by GC-FID analysis,
depending whether an excess of formic acid was used. This reaction requires long
heating, however may be interrupted and resumed as desired.
The hydrolysis of N-formylamphetamine using hydrochloric acid produced
2-amino-l-phenylpropane (amphetamine) hydrochloride in a 3 7 % yield.
49
Table 1: Yields of the reactions in the
conversion of benzaldehyde to amphetamine.
Precursor
Benzaldehyde
1 -Pheny 1-2-nitropropene
1 -Phenyl-2-propanone
N-formylamphetamine
Benzaldehyde
Product
1 -Phenyl-2-nitropropene
1 -Phenyl-2-propanone
N-formylamphetamine
Amphetamine hydrochloride
Amphetamine hydrochloride
Yield
54%
53%
78%
37%
8%
The yields for the four steps in the conversion of benzaldehyde to amphetamine are
listed in Table 1. The yields of specific interest were those for the manufacture of
l-phenyl-2-nitropropene, l-phenyl-2-propanone and the overall yield of the conversion
of benzaldehyde to amphetamine (8%.). The yields for these reactions were unknown
and needed to be determined. The identification and quantitation can be important since
higher penalties apply for larger amounts of a specific drug. The yield of a specific
reaction can also be used to determine the amount of drug for past and future
productions in a seized clandestine laboratory.
This manufacturing technique for amphetamine is relatively simple and requires the
operator to have no prior knowledge of chemistry, offers a good chance of success,
produces acceptable yields and can be accomplished with inexpensive chemical
apparatus. Zinc and ammonium carbonate have been determined as reactants in the
manufacture of amphetamine and should be included in any listing of chemicals and
ancillary materials known to be used in the illicit manufacture of drags.
50
Chapter Seven
Experimental
7. General
Melting points were determined on a Riechert hot stage apparatus and are uncorrected.
Infrared spectra were recorded in the range 4000 to 400 cm"1 as KBr discs for solids
and single bounce attenuated total reflectance (ATR) for oils, using a Bio-Rad FT-IR,
Model FTS 3000 M X .
Nuclear magnetic resonance (NMR) spectra were acquired using a Varian Gemini
200 spectrometer operating at 200 M H z . All N M R spectra were recorded at ambient
temperature in deuterochloroform (CDC13) solution. Chemical shift values are
expressed in p p m relative to deuterochloroform (8 7.26). Signals are described in terms
of chemical shift, multiplicity, coupling constants, intensity and assignment. The
following abbreviations have been used: s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet) or br (broad).
Mass spectra were recorded on a Hewlett-Packard 5890 spectrometer mass selective
detector. The ionization voltage was 70 eV and the source temperature was 300 °C.
The samples were introduced into the mass spectrometer via a gas chromatograph
operated in the split mode (20:1) and equipped with a Hewlett-Packard 12.5-m x 0.20-
m m i.d. fused-silica column with a 0.33-um film thickness of cross linked
methylsiloxane (HP-1). The injector port temperature was 260 °C. The column
temperature was held at 70 °C for 2 minutes and programmed to 310 °C at a rate of 20
°C/minute with a hold time of 6 minutes. Samples for G C - M S were prepared by
removing an aliquot diluting with water, basified with sodium carbonate if necessary
and extracting with dichloromethane. In the description of mass spectra, only
molecular ion peaks (M+), and peaks registering above 1 0 % relative abundance peaks,
or the eight most intense peaks were reported in terms of m/z and relative abundance.
Ions are listed in decreasing order of intensity.
51
Gas Chromatography Flame Ionization Detection Methodology Quantitative
analyses were performed on a Hewlett Packard 5890 gas chromatograph equipped with
a Hewlett Packard HP-1 capillary column, cross linked methyl silicone (20m x 0.2 m m
x 0.33 p m film thickness), equipped with a flame ionization detector operated with a
75:1 split ratio. The injection port temperature was 250 °C, the column temperature
was held at 50 °C for 1 minute and programmed to 300 °C at a rate of 20 °C/minute,
detector set at 250 °C. Helium was used as the carrier gas, nitrogen was used as the
make up gas. A solution of the internal standard was prepared by accurately weighing
approximately lmg acetophenone and dissolving in lOmL of ethyl acetate. The
standard solution of, l-phenyl-2-propanone was prepared by dissolving a known
amount in dichloromethane to give a final concentration of 0.66 mg/mL. For the
determination of P2P in crude reactions, samples were prepared by accurately weighing
approximately 5 m g into appropriate volumetric flasks to produce a final concentration
of 0.5 mg/mL. 50 \\L of the internal standard was added to 1 m L of the diluted sample
and 5 JLIL injected into the column to give a response approximately equal to that of the
standard P2P response. A similar procedure was used in the quantitation of
N-formylamphetamine.
Column chromatography was performed using Merck silica gel 60 with constant
proportions of ethyl acetate in hexane as the eluting solvent. Analytical thin layer
chromatography (T.L.C.) was carried out using Merck (A.T. 5554) silica gel 60 F254
precoated on aluminium sheets. Compounds were routinely detected under short
wavelength (254 n m ) ultraviolet light.
High Performance Liquid Chromatography data was obtained using a Hewlett
Packard instrument (Series 1100) using a LiChroCART 125-2 Merck Superspher R P
Select B (4 p m ) column. Mobile phase consisted of acetonitrile: water: diethylamine
(400:600:5, v/v/v) p H 8.0. Column pressure and temperature were 61 Bar and 45° C
respectively, flow rate 0.155 m L / minute, signal was detected using a photo diode array
detector at wavelength 214 n m (DAD). Quantitative results were based on peak area
using external standards.
52
7.1. Materials
All chemicals were of reagent grade and solvents were of analytical grade. The internal
standard for the GC-FID quantitation, acetophenone, was obtained from Sigma Aldrich.
7.2. Preparation of Compounds
7.2.1. Syntheses of l-Phenyl-2-nitropropene
Ammonium carbonate as Base
(a) To benzaldehyde (10.6 g, 0.1 mol) and nitroethane (7.5 g, 0.1 mol) in acetic
acid (10 mL), ammonium carbonate (0.96 g, 0.01 mol) was added with effervescence
and the yellow solution was heated to reflux for 2 hr. The reaction was monitored by
G C - M S after 1 and 2 hr. The reaction mixture was cooled in an ice water bath, and the
crystalline product (2.85g, 17.5%) was removed by filtration and washed with small
amounts of acetic acid. An additional amount was obtained from the mother liquor.
The crystalline material was recrystallised from methanol, to give l-phenyl-2-
nitropropene (3.66 g, 22.5%), m.p. 63-64° C (lit.1 m.p. 64-65° C).
This reaction was repeated on the ten fold scale to give 1-phenyl-2-nitropropene in
4 7 % yield.
lR NMR (CDC13, 200 MHz) 8: 2.45 (s, 3H, CH3); 7.45 (s, 5H, ArH);
8.1 (s, 1H, vinyl H).
Gas chromatograph retention time: 6.90 minutes.
Mass Spectrum (EI) m/z: 163 (13%, M + ) , 115 (100 % ) , 91 (40%), 105 (32%),
51 (21 % ) , 63(17%), 65(16%), 66 (15 % ) .
Infrared spectrum vm a x / cm"1: Aromatic C-H 3000, C = C 1652, conj N 0 2 1517.
53
(b) To benzaldehyde (7.96 g, 75 mmol) and nitroethane (3.75 g, 50 mmol) in
acetic acid (10 m L ) , ammonium carbonate (1.2 g, 12.5 mmol) was added with
effervescence and the yellow solution was heated under reflux for 6 hr. Cooling the
reaction mixture gave the first crop of crystals (3.46 g, 42%). The mother liquor was
poured into water (200 m L ) and the mixture was extracted with toluene (3 x 30 mL).
The product recovered was subjected to rapid silica filtration (eluent: 1 0 % ethyl
acetate/hexane) to yield an additional 0.97 g (total 4.43 g, 54%).
Butylamine as Base
(a) To benzaldehyde (15.9 g, 0.15 mol) and nitroethane (7.5 g, 0.1 mol) in acetic
acid (10 m L ) , butylamine (1.85 g, 0.025 mol) was added. The yellow solution
was heated to reflux for 3 hr. The reaction mixture was cooled, poured into water
(200 m L ) and extracted with toluene (3 x 50 mL). The organic portion was dried over
anhydrous sodium sulfate and the solvent evaporated. The product was recrystallised
from methanol (7.05 g, 43%). A n additional 1.66 g of product was recovered from the
mother liquor (total 8.66 g, 53%).
(b) To benzaldehyde (3.18 g, 0.03 mol) and nitroethane (1.5 g, 0.02 mol) in acetic
acid (5 m L ) , butylamine (0.15 g, 2 mmol) was added. The reaction mixture was heated
to reflux for 4 hr. The reaction was cooled to room temperature and a small amount of
water (5 m L ) was added dropwise. The precipitate was filtered and rinsed with ice-
cold acetic acid to afford the first crop (1.22 g). The mother liquor was treated as
described above to yield a brown crystalline material. Recrystallisation from methanol
yielded an additional 0.82 g. (total 2.04 g, 62%).
Ammonium carbonate as Base
Experiment based on handwritten notes seized from a clandestine site
To a solution of ammonium carbonate (2.5 g, 26 mmol) in glacial acetic acid (25 mL),
nitroethane was added (7.28 g, 97 mmol) with swirling. Benzaldehyde (10.4 g, 98
mmol) was added and the reaction mixture was heated under reflux for 1 hr. The
reaction mixture was poured onto crushed ice. W h e n the ice had melted, the water was
decanted and the yellow solution was poured into a Buchner funnel where the product
crystallised (6.21 g, 39%).
54
7.2.2. Syntheses of l-Phenyl-2-propanone
The proportion of l-phenyl-2-propanone from each reaction were determined by
GC-FID.
To l-phenyl-2-nitropropene (1.6 g, 0.01 mol) in acetic acid (10 mL), zinc powder
(3.3 g, 0.05 mol) was added portionwise. The reaction mixture evolved gas and heat
turning a red colour. After heating under reflux for 1.5 hr. the mixture was poured into
water (200 mL). The solution was basified with sodium carbonate and was extracted
with dichloromethane (3 x 30 mL). The product recovered was a red oil (1.24 g),
containing l-phenyl-2-propanone (0.26 g; yield 19%).
Gas chromatograph retention time: 4.27 minutes.
Mass Spectrum (EI) m/z: 134 (11%, M + ) , 43(100 % ) , 91 (46%), 65 (19 % ) , 92 (15%),
63 (10%).
Infrared spectrum vm a x / cm"1 Aromatic C-H 3032, C = 0 1713.
Variation in amount of zinc
To four separate test tubes, each containing l-phenyl-2-nitropropene (0.8 g, 5 mmol)
in acetic acid (10 m L ) , zinc powder in 1,2,3 and 4 equivalents was added. These were
heated to 105° C over a 2 hr. period and samples were monitored by G C - M S at 1 hr.
(55°C),2hr. (105 °C).
Other metals
To four separate test tubes, each containing l-phenyl-2-nitropropene (0.8 g, 5 mmol)
in acetic acid (10 m L ) , one equivalent of each metal was added. Sn (0.59 g, 5 mmol),
Al (0.14 g, 5 mmol), Fe (0.28 g, 5 mmol), and Zn (0.33 g, 5 mmol) were added
individually to the different test tubes which were heated to 100-105° C for 2 hr.
Samples were monitored by G C - M S at 1 and 2 hr.
55
T w o phase solvent system
To l-phenyl-2-nitropropene (1.0 g, 6.1 mmol), zinc powder (0.8 g, 12 mmol) in
toluene (10 m L ) , hydrochloric acid (10 m L , 2 M ) was added dropwise. The reaction
mixture was heated to reflux in an oil bath for 3 hr. The reaction mixture was poured
into water (100 m L ) and the product was recovered with toluene to yield a yellow oil
(0.71 g, 53%). Analysis by GC-FID indicated that the product contained
l-phenyl-2-nitropropene (31%), l-phenyl-2-propanone (11%) and l-phenyl-2-
propanone oxime (1%).
Reactivity of l-phenyl-2-propanone
To l-phenyl-2-propanone (1.34 g, 0 01 mol) in acetic acid (10 m L ) , zinc powder
(3.3 g, 0.05 mol) was added. The resulting solution was refluxed for 1 hr. Samples for
G C / M S were taken at 1 hr. Analysis by G C - M S showed only starting material.
Varying the combination of reactants
Zinc powder in acetic acid
To zinc powder (3.3 g, 0.05 mol) in acetic acid (5 m L ) , a solution of l-phenyl-2-
nitropropene (1.6 g, 0.01 mol) in acetic acid (5 m L ) was added in portions. The
resulting solution was refluxed for 12 hr. The reaction mixture was poured into water
(200 m L ) and extracted with toluene (2 x 30 mL). The product recovered was a red oil
(1.36g). Analysis by GC-FID indicated that the product contained l-phenyl-2-
nitropropene (61%) and l-phenyl-2-propanone (6%).
Refluxing solution of zinc powder in acetic acid
To zinc powder (3.3 g, 0.05 mol) in boiling acetic acid (10 m L ) , a solution of 1-phenyl-
2-nitropropene (1.6 g, 0.01 mol) in acetic acid was added down the condenser.
The reaction mixture was heated to reflux for 2 hr. and the reaction was monitored by
G C - M S every 15 min. Recovery of the product with toluene gave a yellow solid
(1.3g,). Analysis by GC-FID indicated that the product contained both l-phenyl-2-
nitropropene (84%) and l-phenyl-2-propanone (23%).
Increasing the reaction time to 4 hours gave 1-phenyl-2-propanone (0.14g, 11%).
56
Extraction with toluene
To l-phenyl-2-nitropropene (1.6 g, O.Olmol) in acetic acid (10 m L ) zinc powder
(3.3 g, 0.05 mol) was added in portions. The reaction mixture was heated to reflux for
2 hr. Recovery of the product with toluene afforded a red oil (1.36 g), containing
l-phenyl-2-propanone (0.37g; yield 27%).
This reaction was repeated on a five fold scale to give a crude product (6.11g)
containing l-phenyl-2-propanone (2.2g; yield 32%).
Synthesis of l-Phenvl-2-propanone
(a) Purification by vacuum distillation
To l-phenyl-2-nitropropene (8.15 g, 0.05 mol) in acetic acid (50 m L ) , zinc powder
(16.34 g, 0.25 mol) was added in portions. Heat was evolved from the reaction
mixture, which turned red from an initial yellow colour. After heating under reflux for
3 hr., an additional 1 equivalent (3.25g) of zinc powder was added and heating was
continued for 2 hr. Recovery of the product with toluene afforded a dark red oil
(7.04g). Vacuum distillation of this oil yielded 1 -phenyl-2-propanone (2.91 g, 4 3 % ) ;
b.p14 100-101 °C (lit.2 b.p14 100-101 °C).
(b) Purification by silica filtration
To l-phenyl-2-nitropropene (1.6 g, 0.01 mol) in acetic acid (10 m L ) , zinc powder
(3.3g, 0.05mol) was added in portions and the mixture was heated under reflux. At 2
hours, an additional equivalent (0.66 g) of zinc powder was added to the mixture and
heating was continued for 1 hr. The reaction was monitored by G C - M S at 0, 1,2,3 hr.
Recovery of the product with toluene afforded a red oil (1.05 g) which was purified by
column chromatography on silica gel (eluent: 1 0 % ethylacetate/hexane), to give
l-phenyl-2-propanone as a yellow oil (0.35 g, 26%).
57
(c) Purification by steam distillation
To l-phenyl-2-nitropropene (32.64 g, 0.2 mol) in acetic acid (200 m L ) , zinc powder
(65.37 g, 1 mol) was added in portions. The yellow solution turned a deep red with
evolution of heat. The mixture was heated under reflux for 2 hr. and monitored by GC-
M S at 1 and 2 hr. Water (100 m L ) was added to the reaction flask and the mixture was
steam distilled to yield l-phenyl-2-propanone as a yellow oil (14.32 g, 53%).
'H NMR (CDC13, 200 MHz) 8: 2.15 (s, 3H, CH3); 3.7 (s, 2H, CH2); 7.3 (m, 5H, ArH).
Gas chromatograph retention time: 4.28 minutes.
Mass Spectrum (EI) m/z: 134 (11%, M + ) , 43(100 % ) , 91 (46%), 65 (19 % ) , 92 (15%),
63 (10%).
Infrared spectrum vm a x / cm'1 Aromatic C-H 3030, C = 0 1709.
Clandestine method (experiment based on handwritten notes)
To a solution of acetic acid (20 m L ) and water (2 mL), zinc powder (2.5 g, 38.3 mmol)
was added. The zinc was allowed to react and l-phenyl-2-nitropropene (2.5 g, 15.3
mmol) was added. The mixture was then heated to reflux for 1 hr. The reaction was
cooled, water (170 m L ) was added and mixture was steam distilled. The distillate was
basified with sodium carbonate, extracted with toluene (2 x 20 m L ) and dried over
anhydrous sodium sulfate. The solvent was evaporated to yield 1-phenyl-2-propanone
as an orange oil (0.8 g, 39%).
One-pot conversion of benzaldehyde to l-phenyl-2-propanone
To benzaldehyde (8.52 g, 0.08 mmol) and nitroethane (4.05 g, 0.054 mol) in acetic
acid (20 m L ) , ammonium carbonate (0.48 g, 5 mmol) was added with effervescence.
The yellow solution was heated to reflux for 1 hr. The reaction mixture was cooled in
a water bath while zinc powder (16.3 g, 0.25 mol) was added slowly (vigorous
reaction). The reaction mixture was refluxed for 1 hr, cooled and poured into water
(200 mL) . The mixture was basified with sodium carbonate and extracted with
dichloromethane (2 x 75 mL). The product recovered was a red oil (6.32 g), which was
distilled to afford l-phenyl-2-propanone (3.17 g, 44%).
58
7.2.3. Syntheses of N-Formylamphetamine
H
7.2.3.1 Leuckart reactions using commercial l-phenyl-2-propanone
Formamide
A solution of l-phenyl-2-propanone (1.34 g, 0.01 mol) and formamide (2.25 g, 0.05
mol) was heated to 160° C under reflux conditions for 7.5 hr. The reaction mixture was
poured into water (100 m L ) and extracted with toluene (3 x 30 mL). The organic
material recovered was an orange oil (1.65 g), that, by GC-MS, appeared to be starting
material.
Increasing the reaction time to 12 hours afforded an orange oil (1.24g). This product
was washed with hexane to give N-formylamphetamine (0.96 g, 59%).
Formamide and formic acid
l-Phenyl-2-propanone (1.34 g, 0.01 mol), formamide (2.25 g, 0.05 mol) and formic
acid (0.46 g, 0.01 mol) were combined and heated to 160° C for 2 hr (reaction over
heated to 200° C). The reaction was monitored by G C - M S every 30 minutes. The
reaction mixture was cooled, poured into water (100 m L ) and extracted with
dichloromethane (3 x 25 mL). The yellow oil (1.20 g) recovered was subjected to
column chromatography on silica gel. Elution with methanol (200 m L ) and
concentrated ammonia (1% v/v) afforded an orange oil (0.74 g). This product was
washed with hexane to give N-formylamphetamine (0.59 g, 36%).
This experiment was repeated refluxing for 4 hours to give N-formylamphetamine
(1.62 g, 99%).
59
This reaction was repeated refluxing for 2.5 hours to give a dark brown oil (1.44g).
The reaction was monitored by G C - M S and appeared essentially complete after 1 hr.
The oil was washed with hexane (3 x 25 m L ) the solvent evaporated to yield a light
brown oil (1.16g, 71%) which appeared to be N-formylamphetamine when analysed by
G C - M S and •H-NMR.
Gas chromatograph retention time: 7.08 minutes.
Mass Spectrum (EI) m/z: 163 (1%, M + ) , 44 (100%), 72 (96%), 118 (84%), 91 (35%),
65(19%), 117(15%).
Infrared spectrum vm a x / cm"1 Aromatic C-H 3000, N-H 3265, C = 0 1651.
Ammonium formate
To l-phenyl-2-propanone (1.34 g, 0.01 mol) in formic acid (2.3 g, 0.05 mol),
ammonium carbonate (4.8 g, 0.05 mol) was added portionwise. The reaction was
heated to reflux for 8 hr. The reaction mixture was cooled, poured into water (100 m L )
and extracted with toluene, then dried over anhydrous sodium sulfate and the solvent
evaporated to give N-formylamphetamine (0.81 g, 50%).
Ammonium formate and excess formic acid (distillation of water)
To l-phenyl-2-propanone (1.34 g, 0.01 mol) in formic acid (8.54 g, 0.19 mol)
ammonium carbonate (4.8 g 0.05 mol) was added portion wise, reagents dissolved upon
heating. Heating was continued for 8 hr at 160° C. The apparatus was changed to a
distillation setup. Water was distilled at 105° C and the reaction was further refluxed
for 3 hr. The reaction was quenched with water (200 mL), basified with sodium
carbonate and extracted with toluene (3 x 30 mL). Removal of the solvent gave
N-formylamphetamine (0.81 g, 50%).
Ammonium formate and excess formic acid
To l-phenyl-2-propanone (1.34 g, 1.34 mL, 0.01 mol) in excess formic acid (8.54 g,
0.19 mol), ammonium carbonate (4.8 g, 0.05 mol) was added portionwise. The
reaction mixture was heated under reflux for 24 hr, and was monitored by G C - M S at
5 and 24 hr. Recovery of the product gave N-formylamphetamine (1.27 g, 78%).
60
1-2.3.2 Leuckart reactions using impure/crude l-phenvl-2-propanone
Yields of N-formylamphetamine are based on the content (32%) of l-phenyl-2-
propanone in the starting material.
Formamide
l-Phenyl-2-propanone (1.34 g, 0.01 mol), formamide (2.25 g, 0.05 mol) were heated
under reflux for 11 hr. The mixture was cooled, poured into water and extracted with
toluene (3 x 30 m L ) , dried over anhydrous sodium sulfate and the solvent evaporated.
The crude product recovered (0.51 g), contained N-formylamphetamine (0.240 g; yield
39%).
Formamide and formic acid
l-Phenyl-2-propanone (1.34 g, 0.01 mol), formamide (2.25 g, 0.05 mol) and formic
acid (0.46 g, 0.38 m L , 0.01 mol) were heated under reflux for 3 hr. The reaction was
monitored by G C - M S every hour. The mixture was cooled, poured into water
(100 m L ) , basified with sodium carbonate, extracted with toluene (3 x 30 mL ) , dried
over anhydrous sodium sulfate and the solvent evaporated. The crude product
recovered (0.78g), contained N-formylamphetamine (0.101 g; yield 19%).
Ammonium formate
To l-phenyl-2-propanone (1.34 g, 0.01 mol), in formic acid (2.3 g, 0.05 mol)
ammonium carbonate (4.8 g. 0.05 mol) was added portionwise. The reaction was
heated under reflux for 14 hr. The crude product recovered (1.57 g), contained
N-formylamphetamine (0.45 g; yield 86%).
Ammonium formate in excess formic acid
To l-phenyl-2-propanone (1.34 g, O.Olmol) in excess formic acid (8.54 g, 0.19 mol)
ammonium carbonate (4.8 g, 0.05 mol) was added portionwise. The reaction was
heated under reflux at a temperature of 160° C for four days at 6 hours a day. The crude
product recovered (1.35 g), contained N-formylamphetamine was (0.405 g; yield 78%).
61
7.2.4 Synthesis of Amphetamine hydrochloride
N-Formylamphetamine (1.31g, 8.03 mmol) and concentrated 10M HCI (lOmL) were
combined and heated to 130° C for 2 hr. The reaction was cooled, poured into water
(200mL). This solution was basified with sodium carbonate and extracted into toluene
(3 x 50mL), then dried over anhydrous sodium sulfate. HCI gas was generated (NaCl
and concentrated sulfuric acid) was bubbled through the solution until a precipitate was
observed, the solvent was evaporated to afford 2-amino-l-phenylpropane hydrochloride
as a brown solid (0.6 g) which was recrystallised from acetone to give a white solid
m.p. 145-147° C (lit.3 146-147° C). H P L C analysis indicated the purity of the
hydrochloride salt to be 82%, the yield of this reaction was (0.49 g, 37%).
[ H N M R (200 M H z ) 8: 1.4 (d, 3H, CH 3), 3.05 (m, 2H, CH 2), 3.55 (m, 1H, CH),
7.3 (m, 5H, ArH).
Gas chromatograph retention time: 4.30 minutes.
Mass Spectrum (EI) m/z: 135 (0.005%, M + ) , 44 (100%), 91 (36%), 65 (27%), 42
(18%), 51 (11%).
Infrared spectrum vm a x / cm"1 Aromatic C-H 3000, N-H 3450.
7.3. References
1. Gairaud, C.B. and Lappin, G.R., "The Synthesis of co-Nitrostyrenes", Journal of
Organic Chemistry, 1953,18, 1-3.
2. The Merck Index Twelfth Edition, 1996, An Encyclopedia of Chemicals. Drugs
and Biologicals, Merck Research Laboratories division of Merck & Co., Inc.,
Whitehouse Station, NJ.
3. Heilbron and Bunbury, 1953, Dictionary of Organic Compounds, Volume 4,
Eyre and Spottiswoode, London.
62
Appendix
'H-NMR
Figure 1.
Figure 2.
Figure 3.
Figure 4.
spectra
1 -Phenyl-2-nitropropene.
1 -Phenyl-2-propanone
N-formylamphetamine
Amphetamine hydrochloride
FT-IR spectra
Figure 5.
Figure 6.
Figure 7.
Figure 8.
1 -Phenyl-2-nitropropene.
1 -Phenyl-2-propanone.
N-formylamphetamine.
Amphetamine hydrochloride
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